Carboxylic derivates

ABSTRACT

The present invention provides a compound of formula I processes for preparing such compounds, their the utility in treating clinical conditions including lipid disorders (dyslipidemias) whether or not associated with insulin resistance, methods for their therapeutic use and pharmaceutical compositions containing them.

FIELD OF THE INVENTION

The present invention relates to certain novel 3-(amino-oxo(alkyl,alkyloxy and alkylthio)phenyl) propanoic and propenoic acid derivatives,to processes for preparing such compounds, to their the utility intreating clinical conditions including lipid disorders (dyslipidemias)whether or not associated with insulin resistance and othermanifestations of the metabolic syndrome, to methods for theirtherapeutic use and to pharmaceutical compositions containing them.

BACKGROUND OF THE INVENTION

The metabolic syndrome including type 2 diabetes mellitus, refers to acluster of manifestations including insulin resistance with accompanyinghyperinsulinaemia, possibly type 2 diabetes mellitus, arterialhypertension, central (visceral) obesity, dyslipidaemia observed asderanged lipoprotein levels typically characterised by elevated VLDL(very low density lipoproteins), small dense LDL particles and reducedHDL (high density lipoprotein) concentrations and reduced fibrinolysis.

Recent epidemiological research has documented that individuals withinsulin resistance run a greatly increased risk of cardiovascularmorbidity and mortality, notably suffering from myocardial infarctionand stroke. In type 2 diabetes mellitus atherosclerosis relatedconditions cause up to 80% of all deaths.

In clinical medicine there is awareness of the need to increase theinsulin sensitivity in patients with the metabolic syndrome and thus tocorrect the dyslipidaemia which is considered to cause the acceleratedprogress of atherosclerosis. However, currently this is not auniversally accepted diagnosis with well-defined pharmacotherapeuticindications.

The S-enantiomer of the compound of formula C below

2-ethoxy-3-[4-(2-{4-methanesulfonyloxyphenyl}ethoxy)phenyl]propanoicacid, is disclosed in PCT Publication Number WO99/62872. This compoundis reported to be a modulator of peroxisome proliferator-activatedreceptors (PPAR, for a review of the PPARs see T. M. Willson et al, JMed Chem 2000, Vol 43, 527) and has combined PPARα/PPARγ agonistactivity (Structure, 2001, Vol 9, 699, P; Cronet et al). This compoundis effective in treating conditions associated with insulin resistance.

Surprisingly a series of compounds has now been found which areselective PPARα modulators.

DESCRIPTION OF THE INVENTION

The present invention provides a compound of formula I

as well as optical isomers and racemates therof as well aspharmaceutically acceptable salts, prodrugs, solvates and crystallineforms thereofwhereinA is situated in the ortho, meta or para position and represents

R is hydrogen;

-   -   —OR^(a), wherein R^(a) represents hydrogen, alkyl, aryl or        alkylaryl;    -   —NR^(a)R^(b), wherein R^(a) and R^(b) are the same or different        and R^(a) is as defined above and R^(b) represents hydrogen,        alkyl, aryl, alkylaryl, cyano, —OH, -Oalkyl, -Oaryl,        -Oalkylaryl, —COR^(c) or —SO₂R^(d), wherein R^(c) represents        hydrogen, alkyl, aryl or alkylaryl and R^(d) represents alkyl,        aryl or alkylaryl;        R¹ is alkyl, aryl, alkenyl, alkynyl, or when A is        R¹ can also be cyano;    -   —OR^(e), wherein R^(e) is alkyl, acyl, aryl or alkylaryl;    -   —O—[CH₂]_(m)—OR^(f), wherein R^(f) represents hydrogen, alkyl,        acyl, aryl or alkylaryl and m represents an integer 1-8;    -   —OCONR^(a)R^(c), wherein R^(a) and R^(c) are as defined above;    -   —SR^(d), wherein R^(d) is as defined above;    -   —SO₂NR^(a)R^(f), wherein R^(f) and R^(a) are as defined above;    -   —SO₂OR^(a), wherein R^(a) is as defined above;    -   —COOR^(d), wherein R^(d) is as defined above;        R² is hydrogen, halogen, alkyl, aryl, or alkylaryl,        R³ and R⁴ are the same or different and each represents        hydrogen, alkyl, aryl, or alkylaryl;        T represents O, S or a single bond;        n represents 1, 2, 3 or 4;        R⁵ and R⁶ are independently selected substituents, comprising C,        H, N, O, S, Se, P or halogen atoms, which give compounds of the        General Formula I a molecular weight <650;        with a first proviso that        when A is CH₂CH(OC₂H₅)COOC₂H₅ or CH₂CH(OC₂H₅)COOH; T is O; n is        1 and R⁵ represents a C₂₋₄alkyl group then R⁶ does not represent        a group of formula        wherein R^(x) represents chloro, trifluoromethyl or        trifluoromethoxy, R^(y) represents H or fluoro;        and a second proviso that when A is CH₂CH(OC₂H₅)COOC₂H₅ or        CH₂CH(OC₂H₅)COOH; T is O; n is 1 and R⁵ represents hexyl or        heptyl then R⁶ does not represent a group of formula        wherein R^(z) represents phenyl, 2,4-difluorophenyl or        cyclohexyl, and n is 1 or 2;        provided that the compound of formula I is not:

-   (2S)-4-[2-[[2-[[(2,6-dichlorophenyl)methyl]thio]ethyl]amino]-2-oxoethoxy]-α-methoxy-benzenepropanoic    acid;

-   (2S)-4-[2-[butyl(1-phenylethyl)amino]-2-oxoethoxy]-α-methoxy-benzenepropanoic    acid;

-   (2S)-α-methoxy-4-[2-oxo-2-[[2-(3-pyridinyl)ethyl]amino]ethoxy]-benzenepropanoic    acid;

-   (2S)-α-methyl-4-[2-oxo-2-[[2-(4phenoxyphenyl)ethyl]amino]ethoxy]-α-phenoxy-benzenepropanoic    acid;

-   (2S)-α-methoxy-4-[2-[(1-methyl-3-phenylpropyl)amino]-2-oxoethoxy]-benzenepropanoic    acid;

-   (2S)-α-methoxy-4-[2-oxo-2-[[2-(4-phenoxyphenyl)ethyl]amino]ethoxy]-benzenepropanoic    acid;

-   (2S)-α-methoxy-4-[2-oxo-2-[4-[4-(trifluoromethyl)phenyl]-1-piperazinyl]ethoxy]-benzenepropanoic    acid;

-   (2S)-4-[2-[[2-(4-bromophenyl)ethyl]amino]-2-oxoethoxy]-α-methoxy-benzenepropanoic    acid;

-   (2S)-4-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]-2-oxoethoxy]-α-methoxy-benzenepropanoic    acid;

-   (2S)-4-[2-[[2-[ethyl(3-methylphenyl)amino]ethyl]amino]-2-oxoethoxy]-α-methoxy-benzenepropanoic    acid;

-   α-methoxy-α-methyl-4-[2-oxo-2-[[2-(4-phenoxyphenyl)ethyl]amino]ethoxy]-benzenepropanoic    acid;

-   (2S)-α-methoxy-4-[2-[(3-methylbutyl)amino]-2-oxoethoxy]-benzenepropanoic    acid;

-   (2S)-4-[2-[4-(diphenylmethyl)-1-piperazinyl]-2-oxoethoxy]-α-methoxy-benzenepropanoic    acid;

-   (2S)-4-[2-(heptylamino)-2-oxoethoxy]-α-methoxy-α-methyl-benzenepropanoic    acid;

-   4-[2-[4-(2-fluorophenyl)-1-piperazinyl]-2-oxoethoxy]-α-methoxy-,    benzenepropanoic acid;

-   (2S)-4-[2-[4-(4-chlorobenzoyl)-1-piperidinyl]-2-oxoethoxy]-α-methoxy-,    benzenepropanoic acid;

-   (2S)-4-[2-[ethyl    [(3-methylphenyl)methyl]amino]-2-oxoethoxy]-α-methoxy-benzenepropanoic    acid;

-   (2S)-α-methoxy-4-[2-oxo-2-[(4-phenoxyphenyl)amino]ethoxy]-benzenepropanoic    acid;

-   (2S)-α-methoxy-4-[2-[(1-methylhexyl)amino]-2oxoethoxy]-benzenepropanoic    acid;

-   (2S)-4-[2-[([1,1′-biphenyl]4-ylmethyl)amino]-2-oxoethoxy]-α-methoxy-benzenepropanoic    acid;

-   3-[2-[[cis-4-(1,1-dimethylethyl)cyclohexyl]amino]-2-oxoethoxy]-α-methoxy-benzenepropanoic    acid;

-   (2S)-4-[2-[4-(3-chlorophenyl)-1-piperazinyl]-2-oxoethoxy]-α-methoxy-benzenepropanoic    acid;

-   (2S)-α-methoxy-4-[2-[methyl[(1S)-1-phenylethyl]amino]-2-oxoethoxy]-benzenepropanoic    acid;

-   (2S)-α-methoxy-4-[2-[4-(4-methylphenyl)-1-piperazinyl]-2-oxoethoxy]-benzenepropanoic    acid;

-   (2S)-α-methoxy-4-[2-[[3-(methylphenylamino)propyl]amino]-2-oxoethoxy]-benzenepropanoic    acid;

-   (2S)-4-[2-(cyclobutylamino)-2-oxoethoxy]-α-methoxy-benzenepropanoic    acid;

-   (2S)-α-methyl-4-[2-oxo-2-[[2-(4-phenoxyphenyl)ethyl]amino]ethoxy]-α-[4-(trifluoromethoxy)phenoxy]-benzenepropanoic    acid;

-   (2S)-4-[2-(heptylamino)-2-oxoethoxy]-α-methoxy-benzenepropanoic    acid;

-   (2S)-4-[2-[4-(4-fluorophenyl)-1-piperazinyl]-2-oxoethoxy]-α-methoxy-benzenepropanoic    acid;

-   (2S)-α-methoxy-4-[2-[[(1S)-1-(1-naphthalenyl)ethyl]amino]-2-oxoethoxy]-benzenepropanoic    acid;

-   (2S)-α-methoxy-4-[2-oxo-2-[[(1R)-1-phenylethyl](phenylmethyl)amino]ethoxy]-benzenepropanoic    acid;

-   (2S)-4-[2-[(3,3-diphenylpropyl)amino]-2-oxoethoxy]-α-methoxy-benzenepropanoic    acid;

-   (2S)-4-[2-[[trans-4-(1,1-dimethylethyl)cyclohexyl]amino]-2-oxoethoxy]-α-methoxy-benzenepropanoic    acid;

-   (2S)-α-methyl-4-[2-oxo-2-[[2-(4-phenoxyphenyl)ethyl]amino]ethoxy]-α-phenoxy-,    ethyl ester-benzenepropanoic acid;

-   (2S)-4-[2-[(2,2,3,3,4,4,4-heptafluorobutyl)amino]-2-oxoethoxy]-α-methoxy-benzenepropanoic    acid;

-   (2S)-4-[2-(3,4-dihydro-2(1H)-isoquinolinyl)-2-oxoethoxy]-α-methoxy-benzenepropanoic    acid;

-   (2S)-3-[2-[[2-(4-ethylphenyl)ethyl]amino]-2-oxoethoxy]-α-methoxy-benzenepropanoic    acid;

-   (2S)-α-methoxy-4-[2-[(1-naphthalenylmethyl)amino]-2-oxoethoxy]-benzenepropanoic    acid;

-   (2S)-4-[2-[[(4-chlorophenyl)phenylmethyl]amino]-2-oxoethoxy]-α-methoxy-benzenepropanoic    acid;

-   (2S)-α-methoxy-4-[2-oxo-2-[[2-(2-pyridinyl)ethyl]amino]ethoxy]-benzenepropanoic    acid;

-   (2S)-α-methoxy-4-[2-oxo-2-[[(1S)-1-phenylethyl]amino]ethoxy]-benzenepropanoic    acid;

-   (2S)-4-[2-(cyclopentylamino)-2-oxoethoxy]-α-methoxy-benzenepropanoic    acid;

-   (2S)-4-[2-[4-[bis(4-fluorophenyl)methyl]-1-piperazinyl]-2-oxoethoxy]-α-methoxy-benzenepropanoic    acid;

-   4-[2-[cyclohexyl[2-(4-ethylphenyl)ethyl]amino]-2-oxoethoxy]-α-ethoxy-benzenepropanoic    acid;

-   (2S)-4-[2-[(1,3-benzodioxol-5-ylmethyl)amino]-2-oxoethoxy]-α-methoxy-benzenepropanoic    acid;

-   D-Phenylalanine,    N-[[4-[(2S)-2-carboxy-2-methoxyethyl]phenoxy]acetyl]-, α-methyl    ester;

-   (2S)-4-[2-[4-[(4-fluorophenyl)methyl]-1-piperazinyl]-2-oxoethoxy]-α-methoxy-benzenepropanoic    acid;

-   α-methoxy-3-[2-oxo-2-[(4-phenoxyphenyl)amino]ethoxy]-benzenepropanoic    acid;

-   (2S)-α-methoxy-4-[2-[(1-methylbutyl)amino]-2-oxoethoxy]-benzenepropanoic    acid;

-   (2S)-α-methoxy-4-[2-[methyl(1-naphthalenylmethyl)amino]-2-oxoethoxy]-benzenepropanoic    acid;

-   (2S)-3-[2-[[trans-4-(1,1-dimethylethyl)cyclohexyl]amino]-2-oxoethoxy]-α-methoxy-benzenepropanoic    acid;

-   (2S)-4-[2-[4-[(4-chlorophenyl)methyl]-1-piperazinyl]-2-oxoethoxy]-α-methoxy-benzenepropanoic    acid;

-   (2S)-4-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]-2-oxoethoxy]-α-methoxy-benzenepropanoic    acid;

-   (2S)-4-[2-[ethyl    [(2-fluorophenyl)methyl]amino]-2-oxoethoxy]-α-methoxy-benzenepropanoic    acid;

-   (2S)-α-methoxy-4-[2-[[2-(4-methoxyphenoxy)ethyl]amino]-2-oxoethoxy]-benzenepropanoic    acid;

-   (2S)-4-[2-[(1,3-dimethylbutyl)amino]-2-oxoethoxy]-α-methoxy-benzenepropanoic    acid;

-   (2S)-α-(4-fluorophenoxy)-α-methyl-4-[2-oxo-2-[[2-(4-phenoxyphenyl)ethyl]amino]ethoxy]-benzenepropanoic    acid;

-   (2S)-4-[2-[(3,3-dimethylbutyl)amino]-2-oxoethoxy]-α-methoxy-benzenepropanoic    acid;

-   (2S)-4-[2-[4-(4-chlorophenyl)-3-methyl-1-piperazinyl]-2-oxoethoxy]-α-methoxy-benzenepropanoic    acid;

-   (2S)-α-methoxy-4-[2-oxo-2-[[(1R)-1-phenylethyl]amino]ethoxy]-benzenepropanoic    acid;

-   (2S)-4-[2-[4-(4-acetylphenyl)-1-piperazinyl]-2-oxoethoxy]-α-methoxy-benzenepropanoic    acid;

-   (2S)-4-[2-[(3-ethoxy-3-oxopropyl)(phenylmethyl)amino]-2-oxoethoxy]-α-methoxy-benzenepropanoic    acid;

-   (2S)-4-[2-[[cis-4-(1,1-dimethylethyl)cyclohexyl]amino]-2-oxoethoxy]-α-methoxy-benzenepropanoic    acid;

-   (2S)-α-ethyl-4-[2-oxo-2-[[2-(4-phenoxyphenyl)ethyl]amino]ethoxy]-α-phenoxy-benzenepropanoic    acid;

-   (2S)-4-[2-(hexylamino)-2-oxoethoxy]-α-methoxy-benzenepropanoic acid;

-   (2S)-α-methoxy-4-[2-oxo-2-[(2-phenylethyl)(phenylmethyl)amino]ethoxy]-benzenepropanoic    acid; or

-   (2S)-4-[2-[ethyl[2-(4-methoxyphenyl)-1-methylethyl]amino]-2-oxoethoxy]-α-methoxy-benzenepropanoic    acid.

According to another aspect the invention provides for a compound offormula I

as well as optical isomers and racemates therof as well aspharmaceutically acceptable salts, prodrugs, solvates and crystallineforms thereof whereinA is situated in the ortho, meta or para position and represents

R is hydrogen;

-   -   —OR^(a), wherein R^(a) represents hydrogen, alkyl, aryl or        alkylaryl;    -   —NR^(a)R^(b), wherein R^(a) and R^(b) are the same or different        and R^(a) is as defined above and R^(b) represents hydrogen,        alkyl, aryl, alkylaryl, cyano, —OH, -Oalkyl, -Oaryl,        -Oalkylaryl, —COR^(c) or —SO₂R^(d), wherein R^(c) represents        hydrogen, alkyl, aryl or alkylaryl and R^(d) represents alkyl,        aryl or alkylaryl;        R¹ is alkyl, aryl, alkenyl, alkynyl, or when A is        R¹ can also be cyano;    -   —OR^(e), wherein R^(e) is alkyl, acyl, aryl or alkylaryl;    -   —O—[CH₂]_(m)—OR^(f), wherein R^(e) represents hydrogen, alkyl,        acyl, aryl or alkylaryl and m represents an integer 1-8;    -   —OCONR^(a)R^(c), wherein R^(a) and R^(c) are as defined above;    -   —SR^(d), wherein R^(d) is as defined above;    -   —SO₂NR^(a)R^(f), wherein R^(f) and R^(a) are as defined above;    -   —SO₂OR^(a), wherein R^(a) is as defined above;    -   —COOR^(d), wherein R^(d) is as defined above;        R² is hydrogen, halogen, alkyl, aryl, or alkylaryl,        R³ and R⁴ are the same or different and each represents        hydrogen, alkyl, aryl, or alkylaryl;        T represents O, S or a single bond;        n represents 1, 2, 3 or 4;        R⁵ and R⁶ are independently selected substituents, comprising C,        H, N, O, S, Se, P or halogen atoms, which give compounds of the        General Formula I a molecular weight <650;        with a first proviso that        when A is CH₂CH(OC₂H₅)COOC₂H₅ or CH₂CH(OC₂H₅)COOH; T is O; n is        1 and R⁵ represents a C₂₋₄alkyl group then R⁶ does not represent        a group of formula        wherein R^(x) represents chloro, trifluoromethyl or        trifluoromethoxy, R^(y) represents H or fluoro;        and a second proviso that when A is CH₂CH(OC₂H₅)COOC₂H₅ or        CH₂CH(OC₂H₅)COOH; T is O; n is 1 and R⁵ represents hexyl or        heptyl then R⁶ does not represent a group of formula        wherein R^(z) represents phenyl, 2,4-difluorophenyl or        cyclohexyl, and n is 1 or 2;        provided that the compound of formula I is not:

-   (2S)-4-[2-[[2-[[(2,6-dichlorophenyl)methyl]thio]ethyl]amino]-2-oxoethoxy]-α-methoxy-benzenepropanoic    acid;

-   (2S)-4-[2-[butyl(1-phenylethyl)amino]-2-oxoethoxy]-α-methoxy-benzenepropanoic    acid;

-   (2S)-α-methoxy-4-[2-oxo-2-[[2-(3-pyridinyl)ethyl]amino]ethoxy]-benzenepropanoic    acid;

-   (2S)-α-methyl-4-[2-oxo-2-[[2-(4-phenoxyphenyl)ethyl]amino]ethoxy]-α-phenoxy-benzenepropanoic    acid;

-   (2S)-α-methoxy-4-[2-[(1-methyl-3-phenylpropyl)amino]-2-oxoethoxy]-benzenepropanoic    acid;

-   (2S)-α-methoxy-4-[2-oxo-2-[[2-(4-phenoxyphenyl)ethyl]amino]ethoxy]-benzenepropanoic    acid;

-   (2S)-α-methoxy-4-[2-oxo-2-[4-[4-(trifluoromethyl)phenyl]-1-piperazinyl]ethoxy]-benzenepropanoic    acid;

-   (2S)-4-[2-[[2-(4-bromophenyl)ethyl]amino]-2-oxoethoxy]-α-methoxy-benzenepropanoic    acid;

-   (2S)-4-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]-2-oxoethoxy]-α-methoxy-benzenepropanoic    acid;

-   (2S)-4-[2-[[2-[ethyl(3-methylphenyl)amino]ethyl]amino]-2-oxoethoxy]3-α-methoxy-benzenepropanoic    acid;

-   α-methoxy-α-methyl-4-[2-oxo-2-[[2-(4-phenoxyphenyl)ethyl]amino]ethoxy]-benzenepropanoic    acid;

-   (2S)-α-methoxy-4-[2-[(3-methylbutyl)amino]-2-oxoethoxy]-benzenepropanoic    acid;

-   (2S)-4-[2-[4-(diphenylmethyl)-1-piperazinyl]-2-oxoethoxy]-α-methoxy-benzenepropanoic    acid;

-   (2S)-4-[2-(heptylamino)-2-oxoethoxy]-α-methoxy-α-methyl-α-benzenepropanoic    acid;

-   4-[2-[4-(2-fluorophenyl)-1-piperazinyl]-2-oxoethoxy]-α-methoxy-,    benzenepropanoic acid;

-   (2S)-4-[2-[4-(4-chlorobenzoyl)-1-piperidinyl]-2-oxoethoxy]-α-methoxy-,    benzenepropanoic acid;

-   (2S)-4-[2-[ethyl    [(3-methylphenyl)methyl]amino]-2-oxoethoxy]-α-methoxy-benzenepropanoic    acid;

-   (2S)-α-methoxy-4-[2-oxo-2-[(4-phenoxyphenyl)amino]ethoxy]-benzenepropanoic    acid;

-   (2S)-α-methoxy-4-[2-[(1-methylhexyl)amino]-2-oxoethoxy]-benzenepropanoic    acid;

-   (2S)-4-[2-[([1,1′-biphenyl]-4-ylmethyl)amino]-2-oxoethoxy]-α-methoxy-benzenepropanoic    acid;

-   3-[2-[[cis-4-(1,1-dimethylethyl)cyclohexyl]amino]-2-oxoethoxy]-α-methoxy-benzenepropanoic    acid;

-   (2S)-4-[2-[4-(3-chlorophenyl)-1-piperazinyl]-2-oxoethoxy]-α-methoxy-benzenepropanoic    acid;

-   (2S)-α-methoxy-4-[2-[methyl[(1S)-1-phenylethyl]amino]-2-oxoethoxy]-benzenepropanoic    acid;

-   (2S)-α-methoxy-4-[2-[4-(4-methylphenyl)-1-piperazinyl]-2-oxoethoxy]-benzenepropanoic    acid;

-   (2S)-α-methoxy-4-[2-[[3-(methylphenylamino)propyl]amino]-2-oxoethoxy]-benzenepropanoic    acid;

-   (2S)-4-[2-(cyclobutylamino)-2-oxoethoxy]-α-methoxy-benzenepropanoic    acid;

-   (2S)-α-methyl-4-[2-oxo-2-[[2-(4-phenoxyphenyl)ethyl]amino]ethoxy]-α-[4-(trifluoromethoxy)phenoxy]-benzenepropanoic    acid;

-   (2S)-4-[2-(heptylamino)-2-oxoethoxy]-α-methoxy-benzenepropanoic    acid;

-   (2S)-4-[2-[4-(4-fluorophenyl)-1-piperazinyl]-2-oxoethoxy]-α-methoxy-benzenepropanoic    acid;

-   (2S)-α-methoxy-4-[2-[[(1S)-1-(1-naphthalenyl)ethyl]amino]-2-oxoethoxy]-benzenepropanoic    acid;

-   (2S)-α-methoxy-4-[2-oxo-2-[[(1R)-1-phenylethyl](phenylmethyl)amino]ethoxy]-benzenepropanoic    acid;

-   (2S)-4-[2-[(3,3-diphenylpropyl)amino]-2-oxoethoxy]-α-methoxy-benzenepropanoic    acid;

-   (2S)-4-[2-[[trans-4-(1,1-dimethylethyl)cyclohexyl]amino]-2-oxoethoxy]-α-methoxy-benzenepropanoic    acid;

-   (2S)-α-methyl-4-[2-oxo-2-[[2-(4-phenoxyphenyl)ethyl]amino]ethoxy]-α-phenoxy-,    ethyl ester-benzenepropanoic acid;

-   (2S)-4-[2-[(2,2,3,3,4,4,4-heptafluorobutyl)amino]-2-oxoethoxy]-α-methoxy-benzenepropanoic    acid;

-   (2S)-4-[2-(3,4-dihydro-2(1H)-isoquinolinyl)-2-oxoethoxy]-α-methoxy-benzenepropanoic    acid;

-   (2S)-3-[2-[[2-(4-ethylphenyl)ethyl]amino]-2-oxoethoxy]-α-methoxy-benzenepropanoic    acid;

-   (2S)-α-methoxy-4-[2-[(1-naphthalenylmethyl)amino]-2-oxoethoxy]-benzenepropanoic    acid;

-   (2S)-4-[2-[[(4-chlorophenyl)phenylmethyl]amino]-2-oxoethoxy]-α-methoxy-benzenepropanoic    acid;

-   (2S)-α-methoxy-4-[2-oxo-2-[[2-(2pyridinyl)ethyl]amino]ethoxy]-benzenepropanoic    acid;

-   (2S)-α-methoxy-4-[2-oxo-2-[[(1S)-1-phenylethyl]amino]ethoxy]-benzenepropanoic    acid;

-   (2S)-4-[2-(cyclopentylamino)-2-oxoethoxy]-α-methoxy-benzenepropanoic    acid;

-   (2S)-4-[2-[4-[bis(4-fluorophenyl)methyl]-1-piperazinyl]-2-oxoethoxy]-α-methoxy-benzenepropanoic    acid;

-   4-[2-[cyclohexyl[2-(4-ethylphenyl)ethyl]amino]-2-oxoethoxy]-α-ethoxy-benzenepropanoic    acid;

-   (2S)-4-[2-[(1,3-benzodioxol-5-ylmethyl)amino]-2-oxoethoxy]-α-methoxy-benzenepropanoic    acid;

-   D-Phenylalanine,    N-[[4-[(2S)-2-carboxy-2-methoxyethyl]phenoxy]acetyl]-, α-methyl    ester;

-   (2S)-4-[2-[4-[(4-fluorophenyl)methyl]-1-piperazinyl]-2-oxoethoxy]-α-methoxy-benzenepropanoic    acid;

-   α-methoxy-3-[2-oxo-2-[(4-phenoxyphenyl)amino]ethoxy]-benzenepropanoic    acid;

-   (2S)-α-methoxy-4-[2-[(1-methylbutyl)amino]-2-oxoethoxy]-benzenepropanoic    acid;

-   (2S)-α-methoxy-4-[2-[methyl(1-naphthalenylmethyl)amino]-2-oxoethoxy]-benzenepropanoic    acid;

-   (2S)-3-[2-[[trans-4-(1,1-dimethylethyl)cyclohexyl]amino]-2-oxoethoxy]-α-methoxy-benzenepropanoic    acid;

-   (2S)-4-[2-[4-[(4-chlorophenyl)methyl]-1-piperazinyl]-2-oxoethoxy]-α-methoxy-benzenepropanoic    acid;

-   (2S)-4-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]-2-oxoethoxy]-α-methoxy-benzenepropanoic    acid;

-   (2S)-4-[2-[ethyl    [(2-fluorophenyl)methyl]amino]-2-oxoethoxy]-α-methoxy-benzenepropanoic    acid;

-   (2S)-α-methoxy-4-[2-[[2-(4methoxyphenoxy)ethyl]amino]-2-oxoethoxy]-benzenepropanoic    acid;

-   (2S)-4-[2-[(1,3-dimethylbutyl)amino]-2-oxoethoxy]-α-methoxy-benzenepropanoic    acid;

-   (2S)-α-(4-fluorophenoxy)-α-methyl-4-[2-oxo-2-[[2-(4-phenoxyphenyl)ethyl]amino]ethoxy]-benzenepropanoic    acid;

-   (2S)-4-[2-[(3,3-dimethylbutyl)amino]-2-oxoethoxy]-α-methoxy-benzenepropanoic    acid;

-   (2S)-4-[2-[4-(4-chlorophenyl)-3-methyl-1-piperazinyl]-2-oxoethoxy]-α-methoxy-benzenepropanoic    acid;

-   (2S)-α-methoxy-4-[2-oxo-2-[[(1R)-1-phenylethyl]amino]ethoxy]-benzenepropanoic    acid;

-   (2S)-4-[2-[4-(4-acetylphenyl)-1-piperazinyl]-2-oxoethoxy]-α-methoxy-benzenepropanoic    acid;

-   (2S)-4-[2-[(3-ethoxy-3-oxopropyl)(phenylmethyl)amino]-2-oxoethoxy]-α-methoxy-benzenepropanoic    acid;

-   (2S)-4-[2-[[cis-4-(1,1-dimethylethyl)cyclohexyl]amino]-2-oxoethoxy]-α-methoxy-benzenepropanoic    acid;

-   (2S)-α-ethyl-4-[2-oxo-2-[[2-(4-phenoxyphenyl)ethyl]amino]ethoxy]-α-phenoxy-benzenepropanoic    acid;

-   (2S)-4-[2-(hexylamino)-2-oxoethoxy]-α-methoxy-benzenepropanoic acid;

-   (2S)-α-methoxy-4-[2-oxo-2-[(2-phenylethyl)(phenylmethyl)amino]ethoxy]-benzenepropanoic    acid;

-   (2S)-4-[2-[ethyl[2-(4-methoxyphenyl)-1-methylethyl]amino]-2-oxoethoxy]-α-methoxy-benzenepropanoic    acid;

-   [[4-[2-oxo-2-[[phenyl[2-(1-piperidinyl)phenyl]methyl]amino]ethyl]phenyl]methyl]-,    diethyl ester-propanedioic acid;

-   4-[2-(heptylamino)-2-oxoethyl]-α,α-dimethyl-, ethyl    ester-benzenepropanoic acid;

-   2-[[4-(2-amino-2-oxoethoxy)phenyl]methylene]-3-oxo-, methyl    ester-butanoic acid;

-   4-[2-[methyl(2-phenylethyl)amino]-2-oxoethyl]-α-phenyl-, ethyl    ester-benzenepropanoic acid;

-   4-[2-(heptylamino)-2-oxoethyl]-(α,α-dimethyl-, ethyl    ester-benzenepropanoic acid;

-   4-[2-[[2-[[(1,1-dimethylethoxy)carbonyl]methylamino]-4-hydroxyphenyl]amino]-2-oxoethoxy]-α-(methylthio)-,    ethyl ester-benzenepropanoic acid;

-   [[4-[2-oxo-2-[[phenyl[2-(1-piperidinyl)phenyl]methyl]aminoethyl]phenyl]methyl]-propanedioic    acid;

-   N-[3-[4-[2-[methyl(2-phenylethyl)amino]-2-oxoethyl]phenyl]-1-oxo-2-phenylpropyl]-,    methyl ester-glycine;

-   4-[2-[methyl(2-phenylethyl)amino]-2-oxoethyl]-α-phenyl-benzenepropanoic    acid;

-   N-[3-[4-[2-[methyl    (2-phenylethyl)amino]-2-oxoethyl]phenyl]-1-oxo-2-phenylpropyl]-glycine;    or    4-[3-[methyl(2-phenylethyl)amino]-3-oxopropyl]-α-phenyl-benzenpropanoic    acid.

Particularly R⁵ and R⁶ are independently selected substituents,comprising C, H, N, O, S or halogen atoms, which give compounds of theGeneral Formula I a molecular weight <650. Alternatively, R⁵ and R⁶ areindependently selected substituents, comprising C, N, O, S, Se, P orhalogen atoms. 10. According to one aspect of the invention, when eitherof R⁵ and R⁶ is hydrogen, the other is not an alkyl.

Particularly R⁵ and R⁶ independently represent hydrogen, C₁₋₃alkyl,C₂₋₁₀-alkenyl or C₂₋₁₀alkynyl each of which is optionally substituted byone or more of the following which may be the same or different:C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl, aryl, heterocyclyl, heteroaryl,C₁₋₈alkoxy (optionally substituted by one or more fluoro),C₃₋₈cycloalkoxy, C₃₋₈cycloalkenyloxy, aryloxy, heterocyclyloxy,heteroaryloxy, C₃₋₈cycloalkyl C₁₋₈alkoxy, aryl C₁₋₈alkoxy, heterocyclylC₁₋₈ alkoxy or heteroaryl C₁₋₈ alkoxy, fluorine or hydroxy and whereineach of these substituents may optionally be substituted on carbon withone or more substituents which may be the same or different and selectedfrom C₁₋₈alkyl, C₃₋₈cycloalkyl (optionally substituted by C₁₋₈alkyl,C₁₋₈alkoxy (optionally substituted by one or more fluoro), halogen,hydroxy, nitro or cyano), aryl (optionally substituted by C₁₋₈alkyl,C₁₋₈alkoxy (optionally substituted by one or more fluoro), halogen,hydroxy, nitro or cyano), heterocyclyl (optionally substituted byC₁₋₆alkyl on any nitrogen), heteroaryl (optionally substituted byC₁₋₈alkyl, C₁₋₈-alkoxy (optionally substituted by one or more fluoro),halogen, hydroxy, nitro or cyano), C₁₋₈alkoxy (optionally substituted byone or more fluoro), C₃₋₈cycloalkoxy, C₃₋₈ cycloalkyl C₁₋₈alkoxy,aryloxy (optionally substituted by C₁₋₈alkyl, C₁₋₈alkoxy (optionallysubstituted by one or more fluoro), halogen, hydroxy, nitro or cyano),aryl C₁₋₈alkoxy (wherein the aryl part is optionally substituted byC₁₋₈alkyl, C₁₋₈alkoxy (optionally substituted by one or more fluoro),halogen, hydroxy, nitro or cyano), halogen, amino, nitro, hydroxy,methylsulfonyl, methylsulfonyloxy, cyano or methylenedioxy,

or R⁵ and R⁶ independently represent C₃-C₈ cycloalkyl; C₃-C₈cycloalkenyl; aryl; heterocyclyl; or heteroaryl; wherein each of thesegroups is optionally substituted by one or more of the following:C₁₋₈alkyl, C₁₋₈alkoxy (optionally substituted by one or more fluoro),halogen, hydroxy, nitro or cyano), aryl (optionally substituted byC₁₋₈alkyl, C₁₋₈alkoxy (optionally substituted by one or more fluoro),halogen, hydroxy, nitro or cyano; or R⁵ and R⁶ together with thenitrogen atom to which they are attached form a single or a fusedheterocyclic system.

Particularly A is CH₂CH(OR^(t))COOR^(m) wherein R^(t) representsC₁₋₄alkyl and wherein R^(m) represents H or C₁₋₄alkyl.

A preferred group of compounds is represented by formula Ia

-   -   as well as optical isomers and racemates therof as well as        pharmaceutically acceptable salts, prodrugs, solvates and        crystalline forms thereof        wherein,        T represents O or a single bond;        n=1 or 2;        R⁵ and R⁶ are independently selected C₁₋₁₀alkyl (optionally        substituted by one or more C₁₋₄alkoxy); C₅₋₇cycloalkylC₁₋₄alkyl        (optionally substituted cyano); benzyl or phenethyl (each of        which is optionally substituted by one or more of the following:        halo; C₁₋₄alkyl; C₁₋₄alkoxy; trifluoromethyl; trifluoromethoxy;        methylenedioxy; phenyl; benzyloxy; methanesulfonyloxy);        indolylmethyl; or thienylmethyl.

In preferred groups of compounds of formula I and formula Ia, R⁵represents C₁₋₁₀alkyl (optionally substituted by one or more C₁₋₄alkoxy)and R⁶ represents benzyl optionally substituted one or more of thefollowing: halo; C₁₋₄alkyl; C₁₋₄alkoxy; trifluoromethyl;trifluoromethoxy; methylenedioxy; phenyl; benzyloxy ormethanesulfonyloxy.

Alternatively n represents 2, 3 or 4.

In other preferred groups of compounds of formula I and Ia R⁵ and R⁶independently represent benzyl optionally substituted one or more of thefollowing: halo; C₁₋₄alkyl; C₁₋₄alkoxy; trifluoromethyl;trifluoromethoxy; methylenedioxy; phenyl; benzyloxy Prmethanesulfonyloxy.

R³ and R⁴ may be the same or different and each represents alkyl, arylor alkylaryl. Alternatively R³ and R⁴ are hydrogen.

In one aspect of the invention R² is hydrogen or fluorine.

A compound of formula VI:

wherein R5, R6 and n is as defined in any of the preceding claims and Xis a leaving group, such as a halide, OSO₂CH₃, OTosyl, ONosyl, OSO₂CF₃,OC(O)OR, OP(O)(OR)₂ or OSO₂OR, particularly chloro or bromo. Formula VIis useful as an intermediate in the process of manufacturing formula I.

The following definitions shall apply throughout the specification andthe appended claims with regard to the group A.

Unless otherwise stated or indicated, the term “alkyl” denotes astraight or branched, substituted or unsubstituted alkyl group havingfrom 1 to 6 carbon atoms or a cyclic alkyl having from 3 to 6 carbonatoms. The term “lower alkyl” denotes a straight or branched,substituted or unsubstituted alkyl group having from 1 to 3 carbon atomsor a cyclic alkyl having 3 carbon atoms. Examples of said alkyl andlower alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl,iso-butyl, sec-butyl, t-butyl and straight- and branched-chain pentyland hexyl as well as cyclopropyl, cyclobutyl, cyclopentyl andcyclohexyl.

Unless otherwise stated or indicated, the term “alkoxy” denotes a groupO-alkyl, wherein alkyl is as defined above.

Unless otherwise stated or indicated, the term “halogen” shall meanfluorine, chlorine, bromine or iodine.

Unless otherwise stated or indicated, the term “aryl” denotes asubstituted or unsubstituted phenyl, furyl, thienyl or pyridyl group, ora fused ring system of any of these groups, such as naphthyl.

Unless otherwise stated or indicated, the term “substituted” denotes analkyl or an aryl group as defined above which is substituted by one ormore alkyl, alkoxy, halogen, amino, thiol, nitro, hydroxy, acyl, aryl orcyano groups.

Unless otherwise stated or indicated, the term “alkylaryl” denotes a

wherein n is an integer 1 to 6 and R^(r) and R^(i) are the same ordifferent and each represents hydrogen or an alkyl or aryl group asdefined above.

Unless otherwise stated or indicated, the term “acyl” denotes a group

wherein R^(j) is hydrogen, alkyl, alkoxy, aryl and alkylaryl as definedabove.

Unless otherwise stated or indicated, the terms “alkenyl” and “alkynyl”denote a straight or branched, substituted or unsubstituted unsaturatedhydrocarbon group having one or more double or triple bonds and having amaximum of 6 carbon atoms, preferably 3 carbon atoms.

Unless otherwise stated or indicated the term “protective group” (R^(p))denotes a protecting group as described in the standard text “Protectinggroups in Organic Synthesis”, 2nd Edition (1991) by Greene and Wuts. Theprotective group may also be a polymer resin such as Wang resin or2-chlorotrityl chloride resin.

For the groups other than A the following definitions apply.

“Cycloalkyl” means a non-aromatic monocyclic or multicyclic ring systemof from 3 carbon atoms up to 10 carbon atoms.

“Aryl” means an aromatic monocyclic or multicyclic ring system of up to14 carbon atoms.

“Heterocycly.” means a non-aromatic monocyclic or multicyclic ringsystem of up to 14 carbon atoms, containing at least one heteroatom.

“Heteroaryl” means an aromatic monocyclic or multicyclic ring system ofup to 14 carbon atoms, containing at least one heteroatom.

The term “prodrug” as used in this specification includes derivatives ofthe carboxylic acid group which are converted in a mammal, particularlya human, into the carboxylic acid group or a salt or conjugate thereof.It should be understood that, whilst not being bound by theory, it isbelieved that most of the activity associated with the prodrugs arisesfrom the activity of the compound of formula I into which the prodrugsare converted. Prodrugs can be prepared by routine methodology wellwithin the capabilities of someone skilled in the art. Various prodrugsof carboxy are known in the art. For examples of such prodrugderivatives, see:

-   a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and    Methods in Enzymology. 42: 309-396, edited by K. Widder, et al.    (Academic Press, 1985);-   b) A Textbook of Drug Design and Development, edited by    Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design and    Application of Prodrugs”, by H. Bundgaard p. 113-191 (1991);-   c) H. Bundgaard, Advanced Drug Delivery Reviews, 8:1-38 (1992);-   d) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77:285    (1988); and-   e) N. Kakeya, et al., Chem Pharm Bull, 32:692 (1984).

The above documents a to e are herein incorporated by reference.

In vivo cleavable esters are just one type of prodrug of the parentmolecule. An in vivo hydrolysable (or cleavable) ester of a compound ofthe formula (I) that contains a carboxy group is, for example, apharmaceutically acceptable ester which is hydrolysed in the human oranimal body to produce the parent acid. Suitable pharmaceuticallyacceptable esters for carboxy include C₁₋₆alkoxymethyl esters, forexample, methoxymethyl; C₁₋₆alkanoyloxymethyl esters, for example,pivaloyloxymethyl; phthalidyl esters;C₃₋₈cycloalkoxycarbonyloxyC₁₋₆alkyl esters, for example,1-cyclohexylcarbonyloxyethyl; 1,3-dioxolen-2-onylmethyl esters, forexample, 5-methyl-1,3-dioxolen-2-onylmethyl; andC₁₋₆alkoxycarbonyloxyethyl esters, for example,1-methoxycarbonyloxyethyl; and may be formed at any carboxy group in thecompounds of this invention.

Specific compounds of the invention are:

-   (2S)-3-(4-{2-[(2,4-Difluorobenzyl)(octyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic    acid-   (2S)-3-(4-{2-[(2,4-Difluorobenzyl)(nonyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic    acid-   (2S)-3-(4-{2-[(2,4-Difluorobenzyl)(4-ethylbenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic    acid-   (2S)-3-(4-{2-[Benzyl    (methyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid-   (2S)-2-Ethoxy-3-[4-(2-{heptyl    [(1-methylindol-2-yl)methyl]amino}-2-oxoethoxy)phenyl]propanoic acid-   (2S)-3-(4{-2-[(2,3-Dimethoxybenzyl)(heptyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic    acid-   (2S)-3-(4-{2-[Butyl(2,3-dimethoxybenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic-   (2S)-3-(4-{2-[(4-Chlorobenzyl)(4-isopropylbenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic    acid-   (2S)-3-(4-{2-[(Cyclohexylmethyl)(2,4-difluorobenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic    acid-   (2S)-2-Ethoxy-3-(4-{2-[ethyl(2-fluorobenzyl)amino]-2-oxoethoxy}phenyl)propanoic    acid-   (2S)-3-(4{-2-[[4-(benzyloxy)benzyl](butyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic    acid-   (2S)-3-(4-{2-[bis(4-Chlorobenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic    acid-   (2S)-3-(4-{2-[(4-tert-Butylbenzyl)(4-chlorobenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic    acid-   (2S)-3-[4-(2-{(4-Chlorobenzyl)    [4-(trifluoromethyl)benzyl]amino}-2-oxoethoxy)phenyl]-2-ethoxypropanoic    acid-   (2S)-3-[4-(2-{bis[4-(Trifluoromethyl)benzyl]amino}-2-oxoethoxy)phenyl]-2-ethoxypropanoic    acid-   (2S)-3-(4-{2-[Benzyl(ethyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic    acid and-   (2S)-3-(4-{2-[(4-tert-Butylbenzyl)(ethyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic    acid-   (2S)-3-(4-{2-[benzyl(4-isopropylbenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic    acid-   (2S)-2-ethoxy-3-(4-{2-[(3-ethoxypropyl)(4-isopropylbenzyl)amino]-2-oxoethoxy}phenyl)propanoic    acid-   (2S)-3-(4-{2-[butyl(4-isopropylbenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic    acid-   (2S)-3-(4-{2-[(2-chlorobenzyl)(heptyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic    acid-   (2S)-2-ethoxy-3-(4-{2-[heptyl(4-isopropylbenzyl)amino]-2-oxoethoxy}phenyl)propanoic    acid-   (2S)-3-(4-{2-[[(4-cyanocyclohexyl)methyl](4-isopropylbenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic    acid-   (2S)-2-ethoxy-3-(4-{2-[(4-isopropylbenzyl)(2-methoxybenzyl)amino]-2-oxoethoxy}phenyl)propanoic    acid-   (2S)-3-(4-{2-[(2-chlorobenzyl)(4-chlorobenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic    acid-   (2S)-3-(4-{2-[(4-chlorobenzyl)(2,3-dimethoxybenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic    acid-   (2S)-3-(4-{2-[(1,3-benzodioxol-5-ylmethyl)(4-ethoxybenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic    acid-   (2S)-3-(4-{2-[(1,3-benzodioxol-5-ylmethyl)(3-bromobenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic    acid-   (2S)-3-[4-(2-{(1,3-benzodioxol-5-ylmethyl)[3-(trifluoromethyl)benzyl]amino}-2-oxoethoxy)phenyl]-2-ethoxypropanoic    acid-   (2S)-3-(4-{2-[(3,5-dimethoxybenzyl)(4-ethoxybenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic    acid-   (2S)-3-(4-{2-[(3-chloro-4-fluorobenzyl)(4-ethoxybenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic    acid-   (2S)-2-ethoxy-3-(4-{2-[(4-ethoxybenzyl)(2-thienylmethyl)amino]-2-oxoethoxy}phenyl)propanoic    acid-   (2S)-3-(4-{2-[benzyl(isopropyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic    acid-   (2S)-3-{4-[2-(dibenzylamino)-2-oxoethoxy]phenyl}-2-ethoxypropanoic    acid-   (2S)-3-(4-{2-[bis(2-methoxyethyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic    acid-   (2S)-2-ethoxy-3-[4-(2-{heptyl[4-(trifluoromethyl)benzyl]amino}-2-oxoethoxy)phenyl]propanoic    acid-   (2S)-2-ethoxy-3-[4-(2-{heptyl[4-(trifluoromethoxy)benzyl]amino}-2-oxoethoxy)phenyl]propanoic    acid-   (2S)-2-ethoxy-3-(4-{2-[(4-ethylbenzyl)(heptyl)amino]-2-oxoethoxy}phenyl)propanoic    acid-   (2S)-3-(4-{2-[(4-tert-butylbenzyl)(heptyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic    acid-   (2S)-2-ethoxy-3-(4-{2-[heptyl(4-isobutylbenzyl)amino]-2-oxoethoxy}phenyl)propanoic    acid-   (2S)-3-(4-{2-[benzyl(heptyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic    acid-   (2S)-2-ethoxy-3-(4-{2-[(4-fluorobenzyl)(heptyl)amino]-2-oxoethoxy}phenyl)propanoic    acid-   (2S)-3-(4-{2-[(4-chlorobenzyl)(heptyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic    acid-   (2S)-3-(4-{2-[(4-bromobenzyl)(heptyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic    acid-   (2S)-3-(4-{2-[butyl(4-ethylbenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic    acid-   (2S)-3-(4-{2-[butyl(4-tert-butylbenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic    acid-   (2S)-3-(4-{2-[butyl(4-isobutylbenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic    acid-   (2S)-3-(4-{2-[benzyl(butyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic    acid-   (2S)-3-(4-{2-[butyl(4-fluorobenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic    acid-   (2S)-3-(4-{2-[(4-bromobenzyl)(butyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic    acid-   (2S)-3-(4-{2-[butyl(2,4-difluorobenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic    acid-   (2S)-3-[4-(2-{(4-chlorobenzyl)[4-(trifluoromethoxy)benzyl]amino}-2-oxoethoxy)phenyl]-2-ethoxypropanoic    acid-   (2S)-3-(4-{2-[(4-chlorobenzyl)(4-ethylbenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic    acid-   (2S)-3-(4-{2-[(4-chlorobenzyl)(4-isobutylbenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic    acid-   (2S)-3-(4-{2-[benzyl(4-chlorobenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic    acid-   (2S)-3-(4-{2-[(4-chlorobenzyl)(4-fluorobenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic    acid-   (2S)-3-(4-{2-[(4-bromobenzyl)(4-chlorobenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic    acid-   (2S)-3-(4-{2-[(4-chlorobenzyl)(2,4-difluorobenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic    acid-   (2S)-2-ethoxy-3-[4-(2-{(4-methylbenzyl)    [4-(trifluoromethyl)benzyl]amino}-2-oxoethoxy)phenyl]propanoic acid-   (2S)-2-ethoxy-3-[4-(2-{(4-methylbenzyl)[4-(trifluoromethoxy)benzyl]amino}-2-oxoethoxy)phenyl]propanoic    acid-   (2S)-2-ethoxy-3-(4-{2-[(4-ethylbenzyl)(4-methylbenzyl)amino]-2-oxoethoxy}phenyl)propanoic    acid-   (2S)-3-(4-{2-[(4-tert-butylbenzyl)(4-methylbenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic    acid-   (2S)-2-ethoxy-3-(4-{2-[(4-isobutylbenzyl)(4-methylbenzyl)amino]-2-oxoethoxy}phenyl)propanoic    acid-   (2S)-3-(4-{2-[benzyl(4-methylbenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic    acid-   (2S)-2-ethoxy-3-(4-{2-[(4-fluorobenzyl)(4-methylbenzyl)amino]-2-oxoethoxy}phenyl)propanoic    acid-   (2S)-3-(4-{2-[(4-chlorobenzyl)(4-methylbenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic    acid-   (2S)-3-(4-{2-[(4-bromobenzyl)(4-methylbenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic    acid-   (2S)-3-(4-{2-[(2,4-difluorobenzyl)(4-methylbenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic    acid    and pharmaceutically acceptable salts thereof.

In the present specification the expression “pharmaceutically acceptablesalts” is intended to define but is not limited to salts with bases.

It will also be understood that certain compounds of the presentinvention may exist in solvated as well as unsolvated forms. It is to beunderstood that the present invention encompasses all such solvatedforms. Certain compounds of the present invention may exist astautomers. It is to be understood that the present invention encompassesall such tautomers.

Methods of Preparation

The compounds of the invention may be prepared as outlined below.However, the invention is not limited to these methods. The compoundsmay also be prepared as described for structurally related compounds inthe prior art. The reactions can be carried out according to standardprocedures or as described in the experimental section. Compounds offormula I may be prepared by reacting a compound of formula II

whereinA is situated in the ortho, meta or para position and represents

in which R¹, R², R³ and R⁴ are as previously defined and R represents—OR^(p), wherein R^(p) is a protecting group for a carboxylic hydroxygroup as described in the standard text “Protective Groups in OrganicSynthesis”, 2^(nd) Edition (1991) by Greene and Wuts, with ade-protecting agent. The protecting group may also be a resin, such asWang resin or 2-chlorotrityl chloride-resin. Protecting groups may beremoved in accordance to techniques that are well known to those skilledin the art. One such protecting group is where —OR^(p) represents aC₁₋₆alkoxy group or an arylalkoxy group eg benzyloxy, such that COR^(p)represents an ester. Such esters can be reacted with a de-protectingagent e.g. a hydrolysing agent, for example lithium hydroxide in amixture of THF and water, at a temperature in the range of 0-100° C. togive compounds of formula I.

Compounds of formula II may be prepared by reacting a compound offormula III

in which A, T and n are as previously defined with a compound of formulaIV

in which R⁵ and R⁶ are as previously defined in an inert solvent, forexample dichloromethane, in the presence of a coupling agent, forexample a carbodimide, eg 1-(3-dimethylaminopropyl)-3-ethylcarbodiimideor oxalyl chloride, optionally in the presence of a base particularlydiisopropylethyl amine, and optionally in the presence of a catalyst,for example a basic catalyst, eg 4-dimethylaminopyridine, at atemperature in the range of −25° C. to 150° C.

Compounds of formulae III and IV may be prepared by methods described inthe Examples or by analogous methods known to those skilled in the art.

Compounds of formula II may be prepared by reacting a compound offormula V

in which A is as previously defined with a compound of formula VI

in which R⁵ and R⁶ are as previously defined and X represents a leavinggroup, for example a halide, OSO₂CH₃, OTosyl, ONosyl, OSO₂CF₃, OC(O)OR,OP(O)(OR)₂ or OSO₂OR, particularly chloro or bromo, in an inert solvent,for example acetonitrile, methyl isobutylketone, N-methylpyrrolidone,toluene, toluene/water, ethanol or isopropylacetate in the presence of abase, for example potassium carbonate, sodium hydroxide ortriethylamine, at a temperature in the range of −25° C. to 150° C.Optionally a catalyst may be used for example iodide or a quartenaryammonium salt, particularly sodium iodide ortetra-n-butylammonium-iodide, -bromide, -acetate or -hydrogensulphate.

Compounds of formulae V and VI may be prepared by methods described inthe Examples or by analogous methods known to those skilled in the art.

Formulae VI can be:

-   2-chloro-N-(2,4-difluorobenzyl)-N-octylacetamide-   2-chloro-N-(2,4-difluorobenzyl)-N-nonylacetamide-   2-chloro-N-(2,4-difluorobenzyl)-N-(4-ethylbenzyl)acetamide-   2-chloro-N-(2,4-difluorobenzyl)-N-methylacetamide-   2-chloro-N-heptyl-N-[(1-methyl-1H-indol-2-yl)methyl]acetamide-   2-chloro-N-(2,3-dimethoxybenzyl)-N-heptyl acetamide-   N-butyl-2-chloro-N-(2,3-dimethoxybenzyl)acetamide-   2-chloro-N-(4-chlorobenzyl)-N-(4-isopropylbenzyl)acetamide-   2-chloro-N-(cyclohexylmethyl)-N-(2,4-difluorobenzyl)acetamide-   2-chloro-N-ethyl-N-(2-fluorobenzyl)acetamide-   N-[4-(benzyloxy)benzyl]-N-butyl-2-chloroacetamide-   2-chloro-N-hexyl-N-(2-phenylethyl)acetamide-   2-chloro-N,N-bis(4-chlorobenzyl)acetamide-   N-(4-tert-butylbenzyl)-2-chloro-N-(4-chlorobenzyl)acetamide-   2-chloro-N-(4-chlorobenzyl)-N-[4-(trifluoromethyl)benzyl]acetamide-   2-chloro-N,N-bis[4-(trifluoromethyl)benzyl]acetamide-   N-benzyl-2-chloro-N-ethylacetamide-   N-(4-tert-butylbenzyl)-2-chloro-N-ethylacetamide-   2-chloro-N-ethyl-N-[4-(trifluoromethyl)benzyl]acetamide-   2-chloro-N-(4-cyclohexylbutyl)-N-(2,4-difluorobenzyl)acetamide-   N-(2-biphenyl-4-ylethyl)-2-chloro-N-(2,4-difluorobenzyl)acetamide-   2-chloro-N-(4-chlorobenzyl)-N-(2-methoxybenzyl)acetamide-   4-{[butyl(chloroacetyl)amino]methyl}phenyl methanesulfonate

Compounds of formulae II, III, IV, V and VI are useful intermediates inthe preparation of compounds of formula I. Compounds of formula II, III,V and VI are herein claimed as a further aspect of the presentinvention. The S-enantiomers of compounds of formula II, III and V arepreferred. The compounds of the invention may be isolated from theirreaction mixtures using conventional techniques.

Persons skilled in the art will appreciate that, in order to obtaincompounds of the invention in an alternative and in some occasions, moreconvenient manner, the individual process steps mentioned hereinbeforemay be performed in different order, and/or the individual reactions maybe performed at different stage in the overall route (i.e. chemicaltransformations may be performed upon different intermediates to thoseassociated hereinbefore with a particular reaction).

The expression “inert solvent” refers to a solvent that does not reactwith the starting materials, reagents, intermediates or products in amanner that adversely affects the yield of the desired product.

Pharmaceutical Preparations

The compounds of the invention will normally be administered via theoral, parenteral, intravenous, intramuscular, subcutaneous or in otherinjectable ways, buccal, rectal, vaginal, transdermal and/or nasal routeand/or via inhalation, in the form of pharmaceutical preparationscomprising the active ingredient either as a free acid, or apharmaceutical acceptable organic or inorganic base addition salt, in apharmaceutically acceptable dosage form. Depending upon the disorder andpatient to be treated and the route of administration, the compositionsmay be administered at varying doses.

Suitable daily doses of the compounds of the invention in therapeuticaltreatment of humans are about 0.0001-100 mg/kg body weight, preferably0.001-10 mg/kg body weight.

Oral formulations are preferred particularly tablets or capsules whichmay be formulated by methods known to those skilled in the art toprovide doses of the active compound in the range of 0.5 mg to 500 mgfor example 1 mg, 3 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg and 250 mg.

According to a further aspect of the invention there is thus provided apharmaceutical formulation including any of the compounds of theinvention, or pharmaceutically acceptable derivatives thereof, inadmixture with pharmaceutically acceptable adjuvants, diluents and/orcarriers.

Pharmacological Properties

The present compounds of formula (I) are useful for the prophylaxisand/or treatment of clinical conditions associated with inherent orinduced reduced sensitivity to insulin (insulin resistance) andassociated metabolic disorders (also known as metabolic syndrome). Theseclinical conditions will include, but will not be limited to, generalobesity, abdominal obesity, arterial hypertension, hyperinsulinaemia,hyperglycaemia, type 2 diabetes and the dyslipidaemia characteristicallyappearing with insulin resistance. This dyslipidaemia, also known as theatherogenic lipoprotein profile, is characterised by moderately elevatednon-esterified fatty acids, elevated very low density lipoprotein (VLDL)triglyceride rich particles, high Apo B levels, low high densitylipoprotein (HDL) levels associated with low apoAI particle levels andhigh Apo B levels in the presence of small, dense, low densitylipoproteins (LDL) particles, phenotype B.

The compounds of the present invention are expected to be useful intreating patients with combined or mixed hyperlipidemias or variousdegrees of hypertriglyceridemias and postprandial dyslipidemia with orwithout other manifestations of the metabolic syndrome.

Treatment with the present compounds is expected to lower thecardiovascular morbidity and mortality associated with atherosclerosisdue to their antidyslipidaemic as well as antiinflammatory properties.The cardiovascular disease conditions include macro-angiopathies ofvarious internal organs causing myocardial infarction, congestive heartfailure, cerebrovascular disease and peripheral arterial insufficiencyof the lower extremities. Because of their insulin sensitizing effectthe compounds of formula I are also expected to prevent or delay thedevelopment of type 2 diabetes from the metabolic syndrome and diabetesof pregnancy. Therefore the development of long-term complicationsassociated with chronic hyperglycaemia in diabetes mellitus such as themicro-angiopathies causing renal disease, retinal damage and peripheralvascular disease of the lower limbs are expected to be delayed.Furthermore the compounds may be useful in treatment of variousconditions outside the cardiovascular system whether or not associatedwith insulin resistance, like polycystic ovarian syndrome, obesity,cancer and states of inflammatory disease including neurodegenerativedisorders such as mild cognitive impairment, Alzheimer's disease,Parkinson's disease and multiple sclerosis.

The compounds of the present invention are expected to be useful incontrolling glucose levels in patients suffering from type 2 diabetes.

The present invention provides a method of treating or preventingdyslipidemias, the insulin resistance syndrome and/or metabolicdisorders (as defined above) comprising the administration of a compoundof formula I to a mammal (particularly a human) in need thereof.

The present invention provides a method of treating or preventing type 2diabetes comprising the administration of an effective amount of acompound of formula I to a mammal (particularly a human) in needthereof.

In a further aspect the present invention provides the use of a compoundof formula I as a medicament.

In a further aspect the present invention provides the use of a compoundof formula I in the manufacture of a medicament for the treatment ofinsulin resistance and/or metabolic disorders.

Combination Therapy

The compounds of the invention may be combined with another therapeuticagent that is useful in the treatment of disorders associated with thedevelopment and progress of atherosclerosis such as hypertension,hyperlipidaemias, dyslipidaemias, diabetes and obesity. The compounds ofthe invention may be combined with another therapeutic agent thatdecreases the ratio of LDL:HDL or an agent that causes a decrease incirculating levels of LDL-cholesterol. In patients with diabetesmellitus the compounds of the invention may also be combined withtherapeutic agents used to treat complications related tomicro-angiopathies.

The compounds of the invention may be used alongside other therapies forthe treatment of metabolic syndrome or type 2 diabetes and itsassociated complications, these include biguanide drugs, for examplemetformin, phenformin and buformin, insulin (synthetic insulinanalogues, amylin) and oral antihyperglycemics (these are divided intoprandial glucose regulators and alpha-glucosidase inhibitors). Anexample of an alpha-glucosidase inhibitor is acarbose or voglibose ormiglitol. An example of a prandial glucose regulator is repaglinide ornateglinide.

In another aspect of the invention, the compound of formula I, or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, may be administered in association with another PPARmodulating agent. PPAR modulating agents include but are not limited toa PPAR alpha and/or gamma and/or delta agonist, or pharmaceuticallyacceptable salts, solvates, solvates of such salts or prodrugs thereof.Suitable PPAR alpha and/or gamma agonists, pharmaceutically acceptablesalts, solvates, solvates of such salts or prodrugs thereof are wellknown in the art. These include the compounds described in WO 01/12187,WO 01/12612, WO 99/62870, WO 99/62872, WO 99/62871, WO 98/57941, WO01/40170, J Med Chem, 1996, 39, 665, Expert Opinion on TherapeuticPatents, 10 (5), 623-634 (in particular the compounds described in thepatent applications listed on page 634) and J Med Chem, 2000, 43, 527which are all incorporated herein by reference. Particularly a PPARalpha and/or gamma agonist refers to BMS 298585, clofibrate,fenofibrate, bezafibrate, gemfibrozil and ciprofibrate; GW 9578,pioglitazone, rosiglitazone, rivoglitazone, balaglitazone, KRP-297,JTT-501, SB 213068, GW 1929, GW 7845, GW 0207, L-796449, L-165041 and GW2433. Particularly a PPAR alpha and/or gamma agonist refers to(S)-2-ethoxy-3-[4-(2-{4-methanesulphonyloxy-phenyl}ethoxy)phenyl]propanoicacid and pharmaceutically acceptable salts thereof.

In addition the combination of the invention may be used in conjunctionwith a sulfonylurea for example: glimepiride, gllibenclamide(glyburide), gliclazide, glipizide, gliquidone, chloropropamide,tolbutamide, acetohexamide, glycopyramide, carbutamide, glibonuride,glisoxepid, glybuthiazole, glibuzole, glyhexamide, glymidine,glypinamide, phenbutamide, tolcylamide and tolazamide. Preferably thesulfonylurea is glimepiride or glibenclamide (glyburide). Morepreferably the sulfonylurea is glimepiride. Therefore the presentinvention includes administration of a compound of the present inventionin conjunction with one, two or more existing therapies described inthis paragraph. The doses of the other existing therapies for thetreatment of type 2 diabetes and its associated complications will bethose known in the art and approved for use by regulatory bodies forexample the FDA and may be found in the Orange Book published by theFDA. Alternatively smaller doses may be used as a result of the benefitsderived from the combination. The present invention also includes acompound of the present invention in combination with acholesterol-lowering agent. The cholesterol-lowering agents referred toin this application include but are not limited to inhibitors of HMG-CoAreductase (3-hydroxy-3-methylglutaryl coenzyme A reductase). Suitablythe HMG-CoA reductase inhibitor is a statin selected from the groupconsisting of atorvastatin, bervastatin, cerivastatin, dalvastatin,fluvastatin, itavastatin, lovastatin, mevastatin, nicostatin,nivastatin, pravastatin and simvastatin, or a pharmaceuticallyacceptable salt, especially sodium or calcium, or a solvate thereof, ora solvate of such a salt. A particular statin is atorvastatin, or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof. A more particular statin is atorvastatin calcium salt.A particularly preferred statin is, however, a compound with thechemical name(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)-amino]-pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoicacid, [also known as(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[N-methyl-N-(methylsulfonyl)-amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoicacid]or a pharmaceutically acceptable salt or solvate thereof, or asolvate of such a salt. The compound(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl-(methylsulfonyl)-amino]-pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoicacid, and its calcium and sodium salts are disclosed in European PatentApplication, Publication No. EP-A-0521471, and in Bioorganic andMedicinal Chemistry, (1997), 5(2), 437444. This latter statin is nowknown under its generic name rosuvastatin.

In the present application, the term “cholesterol-lowering agent” alsoincludes chemical modifications of the HMG-CoA reductase inhibitors,such as esters, prodrugs and metabolites, whether active or inactive.

The present invention also includes a compound of the present inventionin combination with a bile acid sequestering agent, for examplecolestipol or cholestyramine or cholestagel.

The present invention also includes a compound of the present inventionin combination with an inhibitor of the ileal bile acid transport system(IBAT inhibitor).

Suitable compounds possessing IBAT inhibitory activity have beendescribed, see for instance the compounds described in WO 93/16055, WO94/18183, WO 94/18184, WO 96/05188, WO 96/08484, WO 96/16051, WO97/33882, WO 98/07449, WO 98/03818, WO 98/38182, WO 99/32478, WO99/35135, WO 98/40375, WO 99/35153, WO 99/64409, WO 99/64410, WO00/01687, WO 00/47568, WO 00/61568, WO 00/62810, WO 01/68906, DE19825804, WO 00/38725, WO 00/38726, WO 00/38727, WO 00/38728, WO00/38729, WO 01/68906, WO 01/66533, WO 02/32428, WO 02/50051, EP 864582, EP489423, EP549967, EP573848, EP624593, EP624594, EP624595 andEP624596 and the contents of these patent applications are incorporatedherein by reference.

Particular classes of IBAT inhibitors suitable for use in the presentinvention are benzothiepines, and the compounds described in the claims,particularly claim 1, of WO 00/01687, WO 96/08484 and WO 97/33882 areincorporated herein by reference. Other suitable classes of IBATinhibitors are the 1,2-benzothiazepines, 1,4-benzothiazepines and1,5-benzothiazepines. A further suitable class of IBAT inhibitors is the1,2,5-benzothiadiazepines.

One particular suitable compound possessing IBAT inhibitory activity is(3R,5R)-3-butyl-3-ethyl-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepin-8-ylβ-D-glucopyranosiduronic acid (EP 864 582). Other suitable IBATinhibitors include one of:

-   1,1-di    oxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-1′-phenyl-1′-[N′-(carboxymethyl)    carbamoyl]methyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(carboxymethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-1′-phenyl-1′-[N′-(2-sulphoethyl)carbamoyl]methyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-1′-phenyl-1′-[N′-(2-sulphoethyl)carbamoyl]methyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-(2-sulphoethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(2-sulphoethyl)    carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(2-carboxyethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(2-carboxyethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(5-carboxypentyl)    carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(2-carboxyethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{α-[N′-(2-sulphoethyl)carbamoyl]-2-fluorobenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(R)-(2-hydroxy-1-carboxyethyl)carbamoyl]benzyl)    carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(R)-(2-hydroxy-1-carboxyethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-{N—[(R)-α-(N′-{(R)-1-[N″-(R)-(2-hydroxy-1-carboxyethyl)carbamoyl]-2-hydroxyethyl}carbamoyl)benzyl]carbamoylmethoxy}-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{α-[N′-(carboxymethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{α-[N′-((ethoxy)(methyl)phosphoryl-methyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-{N—[(R)-α-(N′-{2-[(hydroxy)(methyl)phosphoryl]ethyl}carbamoyl)benzyl]carbamoylmethoxy}-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(2-methylthio-1-carboxyethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-{N—[(R)-α-(N′-{2-[(methyl)(ethyl)    phosphoryl]ethyl}carbarmoyl)-4-hydroxybenzyl]carbamoylmethoxy}-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-{N—[(R)-α-(N′-{2-[(methyl)(hydroxy)    phosphoryl]ethyl}carbamoyl)-4-hydroxybenzyl]carbamoylmethoxy}-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-1    (R)-α-[(R)-N′-(2-methylsulphinyl-1-carboxyethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methoxy-8-[N-{(R)-α-[N′-(2-sulphoethyl)carbamoyl]4-hydroxybenzyl}carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N—((R)-1-carboxy-2-methylthio-ethyl)carbamoyl]4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N—((S)-1-carboxy-2-(R)-hydroxypropyl)carbamoyl]4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N—((S)-1-carboxy-2-methylpropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N—((S)-1-carboxybutyl)    carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N—((S)-1-carboxypropyl)    carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N—((S)-1-carboxyethyl)    carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N—((S)-1-carboxy-2-(R)-hydroxypropyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-(2-sulphoethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N—((S)-1-carboxyethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N—((R)-1-carboxy-2-methylthioethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-{(S)-1-[N—((S)-2-hydroxy-1-carboxyethyl)carbamoyl]propyl}carbamoyl]benzyl)carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N—((S)-1-carboxy-2-methylpropyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;-   1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N—((S)-1-carboxypropyl)    carbamoyl]4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;-   1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N—((R/S)-α-{N-[1-(R)-2-(S)-1-hydroxy-1-(3,4-dihydroxyphenyl)prop-2-yl]carbamoyl}-4-hydroxybenzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;-   1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-(2-(S)-3-(R)-4-(R)-5-(R)-2,3,4,5,6-pentahydroxyhexyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;    and-   1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-(2-(S)-3-(R)-4-(R)-5-(R)-2,3,4,5,6-pentahydroxyhexyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;    or a pharmaceutically acceptable salt, solvate, solvate of such a    salt or a prodrug thereof.

According to an additional further aspect of the present invention thereis provided a combination treatment comprising the administration of aneffective amount of a compound of the formula I, or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereof,optionally together with a pharmaceutically acceptable diluent orcarrier, with the simultaneous, sequential or separate administrationone or more of the following agents selected from:

a CETP (cholesteryl ester transfer protein) inhibitor, for example thosereferenced and described in WO 00/38725 page 7 line 22-page 10, line 17which are incorporated herein by reference;

a cholesterol absorption antagonist for example azetidinones such as SCH58235 and those described in U.S. Pat. No. 5,767,115 which areincorporated herein by reference;

a MTP (microsomal transfer protein) inhibitor for example thosedescribed in Science, 282, 751-54, 1998 which are incorporated herein byreference;

a nicotinic acid derivative, including slow release and combinationproducts, for example, nicotinic acid (niacin), acipimox and niceritrol;

a phytosterol compound for example stanols;

probucol;

an omega-3 fatty acid for example Omacor™;

an anti-obesity compound for example orlistat (EP 129,748) andsibutramine (GB 2,184,122 and U.S. Pat. No. 4,929,629);

an antihypertensive compound for example an angiotensin convertingenzyme (ACE) inhibitor, an angiotensin II receptor antagonist, anandrenergic blocker, an alpha andrenergic blocker, a beta andrenergicblocker for example metoprolol, a mixed alpha/beta andrenergic blocker,an andrenergic stimulant, calcium channel blocker, an AT-1 blocker, asaluretic, a diuretic or a vasodilator;

a CB1 antagonist or inverse agonist for example as described inWO01/70700 and EP 65635;

a Melanin concentrating hormone (MCH) antagonist;

a PDK inhibitor; or

modulators of nuclear receptors for example LXR, FXR, RXR, and RORalpha;

or a pharmaceutically acceptable salt, solvate, solvate of such a saltor a prodrug thereof, optionally together with a pharmaceuticallyacceptable diluent or carrier to a warm-blooded animal, such as man inneed of such therapeutic treatment.

Particular ACE inhibitors or pharmaceutically acceptable salts,solvates, solvate of such salts or a prodrugs thereof, including activemetabolites, which can be used in combination with a compound of formulaI include but are not limited to, the following compounds: alacepril,alatriopril, altiopril calcium, ancovenin, benazepril, benazeprilhydrochloride, benazeprilat, benzoylcaptopril, captopril,captopril-cysteine, captopril-glutathione, ceranapril, ceranopril,ceronapril, cilazapril, cilazaprilat, delapril, delapril-diacid,enalapril, enalaprilat, enapril, epicaptopril, foroxymithine,fosfenopril, fosenopril, fosenopril sodium, fosinopril, fosinoprilsodium, fosinoprilat, fosinoprilic acid, glycopril, hemorphin-4,idrapril, imidapril, indolapril, indolaprilat, libenzapril, lisinopril,lyciumin A, lyciumin B, mixanpril, moexipril, moexiprilat, moveltipril,muracein A, muracein B, muracein C, pentopril, perindopril,perindoprilat, pivalopril, pivopril, quinapril, quinapril hydrochloride,quinaprilat, ramipril, ramiprilat, spirapril, spirapril hydrochloride,spiraprilat, spiropril, spiropril hydrochloride, temocapril, temocaprilhydrochloride, teprotide, trandolapril, trandolaprilat, utibapril,zabicipril, zabiciprilat, zofenopril and zofenoprilat. Preferred ACEinhibitors for use in the present invention are ramipril, ramiprilat,lisinopril, enalapril and enalaprilat. More preferred ACE inhibitors foruses in the present invention are ramipril and ramiprilat.

Preferred angiotensin II antagonists, pharmaceutically acceptable salts,solvates, solvate of such salts or a prodrugs thereof for use incombination with a compound of formula I include, but are not limitedto, compounds: candesartan, candesartan cilexetil, losartan, valsartan,irbesartan, tasosartan, telmisartan and eprosartan. Particularlypreferred angiotensin II antagonists or pharmaceutically acceptablederivatives thereof for use in the present invention are candesartan andcandesartan cilexetil.

Therefore in an additional feature of the invention, there is provided amethod for for the treatment of type 2 diabetes and its associatedcomplications in a warm-blooded animal, such as man, in need of suchtreatment which comprises administering to said animal an effectiveamount of a compound of formula I, or a pharmaceutically acceptablesalt, solvate, solvate of such a salt or a prodrug thereof insimultaneous, sequential or separate administration with an effectiveamount of one the other compounds described in this combination section,or a pharmaceutically acceptable-salt, solvate, solvate of such a saltor a prodrug thereof.

Therefore in an additional feature of the invention, there is provided amethod of treating hyperlipidemic conditions in a warm-blooded animal,such as man, in need of such treatment which comprises administering tosaid animal an effective amount of a compound of formula I, or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof in simultaneous, sequential or separate administrationwith an effective amount of one the other compounds described in thiscombination section or a pharmaceutically acceptable salt, solvate,solvate of such a salt or a prodrug thereof.

According to a further aspect of the invention there is provided apharmaceutical composition which comprises a compound of formula I, or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, and one of the other compounds described in thiscombination section or a pharmaceutically acceptable salt, solvate,solvate of such a salt or a prodrug thereof, in association with apharmaceutically acceptable diluent or carrier.

According to a further aspect of the present invention there is provideda kit comprising a compound of formula I, or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereof,and one of the other compounds described in this combination section ora pharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof.

According to a further aspect of the present invention there is provideda kit comprising:

a) a compound of formula I, or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof, in a first unitdosage form;

b) one of the other compounds described in this combination section or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof; in a second unit dosage form; and

c) container means for containing said first and second dosage forms.

According to a further aspect of the present invention there is provideda kit comprising:

a) a compound of formula I, or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof, together with apharmaceutically acceptable diluent or carrier, in a first unit dosageform;

b) one of the other compounds described in this combination section or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, in a second unit dosage form; and

c) container means for containing said first and second dosage forms.

According to another feature of the invention there is provided the useof a compound of the formula I, or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof, and one of theother compounds described in this combination section, or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, in the manufacture of a medicament for use in the thetreatment of metabolic syndrome or type 2 diabetes and its associatedcomplications in a warm-blooded animal, such as man.

According to another feature of the invention there is provided the useof a compound of the formula I, or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof, and one of theother compounds described in this combination section, or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, in the manufacture of a medicament for use in thetreatment of hyperlipidaemic conditions in a warm-blooded animal, suchas man.

According to a further aspect of the present invention there is provideda combination treatment comprising the administration of an effectiveamount of a compound of the formula I, or a pharmaceutically acceptablesalt, solvate, solvate of such a salt or a prodrug thereof, optionallytogether with a pharmaceutically acceptable diluent or carrier, with thesimultaneous, sequential or separate administration of an effectiveamount of one of the other compounds described in this combinationsection, or a pharmaceutically acceptable salt, solvate, solvate of sucha salt or a prodrug thereof, optionally together with a pharmaceuticallyacceptable diluent or carrier to a warm-blooded animal, such as man inneed of such therapeutic treatment.

EXAMPLES

¹H NMR and ¹³C NMR measurements were performed on a Varian Mercury 300or Varian UNITY plus 400, 500 or 600 spectrometers, operating at ¹Hfrequencies of 300, 400, 500 and 600 MHz, respectively, and at ¹³Cfrequencies of 75, 100, 125 and 150 MHz, respectively. Measurements weremade on the delta scale (δ).

Unless otherwise stated, chemical shifts are given in ppm with thesolvent as internal standard.

Abbreviations

DMSO dimethyl sulfoxide

THF tetrahydrofuran

Pd/C palladium on charcoal

DMAP dimethylaminopyridine

t triplet

s singlet

d doublet

q quartet

m multiplet

bs broad singlet

dm doublet of multiplet

bt broad triplet

dd doublet of doublet

Example 1(2S)-3-(4-{2-[(2,4-Difluorobenzyl)(octyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoicacid (i) N-(2,4-Difluorobenzyl)octanamide

To a solution of 2,4-difluorobenzylamine (0.43 g, 3.0 mmol) in methylenechloride (30 mL) were added octanoic acid (0.43 g, 3.0 mmol) and DMAP(0.37 g, 3.0 mmol) followed by1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.60 g, 3.1mmol) and the reaction mixture was stirred at room temperatureovernight. The resulting solution was diluted with methylene chloride(100 mL) and the organic phase was washed with 5% HCl (3×75 mL), aqueousNaHCO₃ (75 mL), and brine (75 mL) and dried over anhydrousNa₂SO₄—Concentration in vacuo afforded 0.78 g (96%) of an oil, whichsolidified upon standing.

¹H NMR (500 MHz, CDCl₃): δ 0.81-0.90 (m, 3H), 1.18-1.33 (m, 8H),1.54-1.66 (m, 2H), 2.12-2.21 (m, 2H), 4.42 (d, 2H), 5.82 (bs, 1H),6.73-6.87 (m, 2H), 7.32 (m, 1H).

(ii) N-(2,4-Difluorobenzyl)-N-octylamine hydrochloride

N-(2,4-Difluorobenzyl)octanamide (0.64 g, 2.4 mmol) was dissolved infreshly distilled THF (20 mL) and cooled on an ice bath under an argonatmosphere. Borane (3.0 mL of a 2 M solution of the dimethylsulfidecomplex in diethyl ether) was added and the ice bath was removed after15 minutes. The reaction mixture was refluxed for twenty hours and wasthen allowed to cool to room temperature. The reaction was quenched bycareful addition of 10% HCl (1.2 mL) and the mixture was stirredovernight and then concentrated in vacuo. Addition of ice cold THF (15mL) afforded a white precipitate, which was filtered off and dried invacuo to give 0.40 g (58%) of a white salt.

¹H NMR (400 MHz, CD₃OD): δ 0.85-0.93 (m, 3H), 1.20-1.45 (m, 10H),1.65-1.89 (m, 2H), 3.01-3.09 (m, 2H), 4.25 (s, 2H), 7.04-7.16 (m, 2H),7.63 (m, 1H).

(iii) Ethyl(2S)-3-(4-{2-[(2,4-difluorobenzyl)(octyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoate

To a solution of {4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic acid(0.120 g, 0.40 mmol) in methylene chloride (5.0 mL) were addedN-(2,4-difluorobenzyl)-N-octylamine hydrochloride (0.165 g, 0.57 mmol),DMAP (0.054 g, 0.45 mmol) and N,N-diisopropylethylamine (0.078 mL, 0.45mmol) followed by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (0.085 g, 0.45 mmol) and the reaction mixture was stirredat room temperature overnight. The resulting solution was diluted withmethylene chloride (50 mL) and the organic phase was washed with 5% HCl(3×25 mL), aqueous NaHCO₃ (25 mL), and brine (25 mL), dried overanhydrous Na₂SO₄, and concentrated in vacuo. Purification on a prepackedcolumn of silica gel (Isolute® SPE Column, 5 g Si/25 mL) with methanol(0-1% gradient) in methylene chloride as the eluent afforded 0.082 g(38%) of a colourless oil.

¹H NMR (400 MHz, CDCl₃): δ 0.80-0.90 (m, 3H), 1.14 (t, 3H), 1.17-1.30(m, 13H), 1.42-1.64 (m, 2H), 2.86-3.00 (m, 2H), 3.20-3.40 (m, 3H), 3.59(m, 1H), 3.95 (m, 1H), 4.15 (q, 2H), 4.59 (s, 2H), 4.69 and 4.70 (2s,2H, rotamers), 6.71-6.88 (m, 4H), 7.07-7.18 and 7.20-7.31 (2m, 3H,rotamers).

(iv)(2S)-3-(4-{2-[(2,4-Difluorobenzyl)(octyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoicacid

To a solution of ethyl(2S)-3-(4-{2-[(2,4-difluorobenzyl)(octyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoate(0.038 g, 0.071 mmol) in THF (3 mL) was added aqueous 0.10 M LiOH (2 mL)and the reaction mixture was stirred at room temperature overnight.After acidification with 5% HCl, the mixture was extracted with ethylacetate (3×25 mL) and the combined organic phase was washed with brine(25 mL), dried over anhydrous Na₂SO₄, and concentrated in vacuo toafford 0.035 g (98%) of a colourless oil.

¹H NMR (400 MHz, CDCl₃): δ0.83-4.93 (m, 3H), 1.17 (t, 3H), 1.20-1.35 (m,10H), 1.42-1.68 (m, 2H), 2.88-3.10 (m, 2H), 3.24-3.35 (m, 2H), 3.41 (m,1H), 3.62 (m, 1H), 4.03 (m, 1H), 4.62 (s, 2H), 4.72 and 4.73 (2s, 2H,rotamers), 6.70-6.90 (m, 4H), 7.09-7.21 and 7.24-7.34 (2m, 3H,rotamers).

Example 2(2S)-3-(4-{2-[(2,4-Difluorobenzyl)(nonyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoicacid (i) N-(2,4-Difluorobenzyl)nonanamide

To a solution of 2,4-difluorobenzylamine (0.47 g, 3.3 mmol) in methylenechloride (30 mL) were added nonanoic acid (0.52 g, 3.3 mmol) and DMAP(0.40 g, 3.3 mmol) followed by1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.67 g, 3.5mmol) and the reaction mixture was stirred at room temperatureovernight. The resulting solution was diluted with methylene chloride(100 mL) and the organic phase was washed with 5% HCl (3×75 mL), aqueousNaHCO₃ (75 mL), and brine (75 mL) and dried over anhydrous Na₂SO₄.Concentration in vacuo afforded 0.87 g (93%) of an oil, which solidifiedupon standing.

¹H NMR (600 MHz, CDCl₃): δ 0.80-0.86 (m, 3H), 1.16-1.28 (m, 10H),1.53-1.62 (m, 2H), 2.11-2.17 (m, 2H), 4.37 (d, 2H), 6.12 (bs, 1H),6.70-6.81 (m, 2H), 7.27 (m, 1H).

(ii) (N-(2,4-Difluorobenzyl)-N-nonylamine hydrochloride

N-(2,4-Difluorobenzyl)nonanamide (0.75 g, 2.6 mmol) was dried once byazeotropic distillation with toluene, dissolved in freshly distilled THF(23 mL), and cooled on an ice bath under an argon atmosphere. Borane(3.3 mL of a 2 M solution of the dimethylsulfide complex in diethylether) was added and the ice bath was removed after 15 minutes. Thereaction mixture was refluxed for five hours and was then allowed tocool to room temperature. The reaction was quenched by careful additionof 10% HCl (1.3 mL) and the mixture was stirred for three hours and thenconcentrated in vacuo. Addition of ice cold THF (15 mL) afforded a whiteprecipitate, which was filtered off and dried in vacuo to give 0.69 g(85%) of a white salt.

¹H NMR (400 MHz, CD₃OD): δ 0.85-0.94 (m, 3H), 1.20-1.45 (m, 12H),1.65-1.80 (m, 2H), 3.00-3.10 (m, 2H), 4.26 (s, 2H), 7.04-7.16 (m, 2H),7.64 (m, 1H).

(iii) Ethyl(2S)-3-(4-{2-[(2,4-difluorobenzyl)(nonyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoate

To a solution of {4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic acid(0.120 g, 0.40 mmol) in methylene chloride (5.0 mL) were added(N-(2,4-difluorobenzyl)-N-nonylamine hydrochloride (0.173 g, 0.57 mmol),DMAP (0.058 g, 0.45 mmol), and N,N-diisopropylethylamine (0.078 mL, 0.45mmol) followed by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (0.085 g, 0.45 mmol) and the reaction mixture was stirredat room temperature overnight. The resulting solution was diluted withmethylene chloride (50 mL) and the organic phase was washed with 5% HCl(3×25 mL), aqueous NaHCO₃ (25 mL), and brine (25 mL), dried overanhydrous Na₂SO₄, and concentrated in vacuo. Purification on a prepackedcolumn of silica gel (Isolute® SPE Column, 5 g Si/25 mL) with methanol(0-1% gradient) in methylene chloride as the eluent afforded 0.117 g(53%) of a colourless oil.

¹H NMR (400 MHz, CDCl₃): δ 0.82-0.90 (m, 3H), 1.14 (t, 3H), 1.17-1.30(m, 15H), 1.42-1.62 (m, 2H), 2.88-3.00 (m, 2H), 3.23-3.38 (m, 3H), 3.58(m, 1H), 3.95 (m, 1H), 4.14 (q, 2H), 4.59 (s, 2H), 4.68 and 4.69 (2s,2H, rotamers), 6.70-6.90 (m, 4H), 7.06-7.18 and 7.20-7.31 (2m, 3H,rotamers).

(iv)(2S)-3-(4-{2-[(2,4-Difluorobenzyl)(nonyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoicacid

To a solution of ethyl(2S)-3-(4-{2-[(2,4-difluorobenzyl)(nonyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoate(0.038 g, 0.070 mmol) in THF (3 mL) was added aqueous 0.10 M LiOH (2 mL)and the reaction mixture was stirred at room temperature overnight.After acidification with 5% HCl, the mixture was extracted with ethylacetate (3×25 mL) and the combined organic phase was washed with brine(25 mL), dried over anhydrous Na₂SO₄, and concentrated in vacuo toafford 0.034 g (94%) of a colourless oil.

¹H NMR (400 MHz, CDCl₃): δ 0.83-0.93 (m, 3H), 1.17 (t, 3H), 1.20-1.35(m, 12H), 1.144-1.66 (m, 2H), 2.90-3.10 (m, 2H), 3.25-3.34 (m, 2H), 3.42(m, 1H), 3.62 (m, 1H), 4.04 (m, 1H), 4.62 (s, 2H), 4.72 and 4.73 (2s,2H, rotamers), 6.73-6.90 (m, 4H), 7.09-7.21 and 7.24-7.34 (2m, 3H,rotamers).

Example 3(2S)-3-(4-{2-[(2,4-Difluorobenzyl)(4-ethylbenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoicacid (i) N-(2,4-Difluorobenzyl)-4-ethylbenzamide

To a solution of 2,4-difluorobenzylamine (3.58 g, 25.0 mmol) inmethylene chloride (250 mL) were added 4-ethylbenzoic acid (3.94 g, 26.3mmol) and DMAP (3.36 g, 27.5 mmol) followed by1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (5.27 g,27.5 mmol) and the reaction mixture was stirred at room temperatureovernight. The resulting solution was washed with 5% HCl (3×100 mL),saturated aqueous NaHCO₃ (100 mL), and brine (100 mL) and dried overNa₂SO₄. Concentration in vacuo afforded 6.49 g (94%) of white solid.

¹H NMR (400 MHz, CDCl₃): δ 1.24 (t, 3H), 2.69 (q, 2H), 4.64 (d, 2H),6.45 (bs, 1H), 6.77-6.90 (m, 2H), 7.25 (d, 2H), 7.41 (m, 1H), 7.69 (d,2H).

(ii) N-(2,4-Difluorobenzyl)-N-(4-ethylbenzyl)amine

N-(2,4-Difluorobenzyl)-4-ethylbenzamide (6.20 g, 22.5 mmol) wasdissolved in freshly distilled THF (220 mL) and cooled in an ice bathunder an argon atmosphere. Borane (28 mL of a 2 M solution of thedimethylsulfide complex in diethyl ether) was added and the ice bath wasremoved after 15 minutes. The reaction mixture was refluxed overnightand was then allowed to cool to room temperature. The reaction wasquenched at 0° C. by careful addition of 10% HCl (11 mL) and the mixturewas stirred at room temperature for three hours and then concentrated invacuo. The residue was taken up in ethyl acetate (200 mL) and aqueous 2M K₂CO₃ (200 mL) and the phases were separated. The aqueous phase wasextracted with ethyl acetate (2×200 mL) and the combined organic phasewas washed with brine (100 mL), dried over Na₂SO₄, and concentrated invacuo to afford 5.56 g (94%) of a yellow oil.

¹H NMR (400 MHz, CDCl₃): δ 1.24 (t, 3H), 2.65 (q, 2H), 3.77 (s, 2H),3.82 (s, 2H), 6.75-6.90 (m, 2H), 7.17 (d, 2H), 7.25 (d, 2H), 7.34 (m,1H).

(iii) Ethyl(2S)-3-(4-{2-[(2,4-difluorobenzyl)(4-ethylbenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoate

To a solution of {4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic acid(1.48 g, 5.0 mmol) and N-(2,4-difluorobenzyl)-N-(4-ethylbenzyl)amine(1.57 g, 6.0 mmol) in methylene chloride (50 mL) at 0° C. were addedN,N-diisopropylethylamine (2.0 mL, 11.5 mmol) followed byO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(1.93 g, 6.0 mmol) and the reaction mixture was stirred overnight andthen concentrated in vacuo. The residue was taken up in ethyl acetate(200 mL) and the organic phase was washed with 5% HCl (3×100 mL),saturated aqueous NaHCO₃ (100 mL), and brine (100 mL), dried overNa₂SO₄, and concentrated in vacuo. Purification on silica gel (240 g)with methanol (0-4% gradient) in methylene-chloride as the eluent andcollection of pure fractions afforded 1.18 g (44%) of a colourless oil.

¹H NMR (400 MHz, CDCl₃): δ 1.16 (t, 3H), 1.19-1.27 (m, 6H), 2.57-2.70(m, 2H), 2.90-3.00 (m, 2H), 3.35 (m, 1H), 3.60 (m, 1H), 3.96 (m, 1H),4.16 (q, 2H), 4.52, 4.54, 4.56 and 4.59 (4s, 4H, rotamers), 4.74 and4.80 (2s, 2H, rotamers), 6.69-6.88 (m, 4H), 7.02-7.22 and 7.25-7.36 (2m,7H, rotamers).

(iv)(2S)-3-(4-{2-[(2,4-Difluorobenzyl)(4-ethylbenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoicacid

To a solution of ethyl(2S)-3-(4-{2-[(2,4-difluorobenzyl)(4-ethylbenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoate(1.13 g, 2.1 mmol) in acetonitrile (100 mL) was added aqueous 0.10 MLiOH (52 mL) and the solution was stirred at room temperature overnight.After neutralisation with 5% HCl, the solvent volume was reduced invacuo and the remaining aqueous phase was acidified with 5% HCl andextracted with ethyl acetate (3×100 mL). The combined organic phase waswashed with brine (100 mL), dried over Na₂SO₄, and concentrated in vacuoto afford 1.01 g (94%) of a colourless oil.

¹H NMR (400 MHz, CDCl₃): δ 1.16 (t, 3H), 1.19-1.28 (m, 3H), 2.56-2.71(m, 2H), 2.95 (m, 1H), 3.05 (m, 1H), 3.41 (m, 1H), 3.61 (m, 1H), 4.02(m, 1H), 4.52, 4.54, 4.55 and 4.59 (4s, 4H, rotamers), 4.75 and 4.81(2s, 2H, rotamers), 6.70-6.88 (m, 4H), 7.04-7.22 and 7.25-7.35 (2m, 7H,rotamers), 8.04 (bs, 1H).

Example 4(2S)-3-(4-{2-[Benzyl(methyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoicacid (i) Ethyl(2S)-3-(4-{2-[benzyl(methyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoate

To a solution of {4-[(2S)-2,3-diethoxy-3-oxopropyl}phenoxy]acetic acid(0.320 g, 1.08 mmol) in methylene chloride (10 mL) were addedN-methylbenzylamine (0.145 g, 1.20 mmol) andO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(0.353 g, 1.10 mmol) and the reaction mixture was stirred at roomtemperature for three days. The resulting solution was diluted withmethylene chloride (100 mL) and the organic phase was washed with 5% HCl(3×50 mL), aqueous NaHCO₃ (50 mL) and brine (50 mL), dried overanhydrous Na₂SO₄, and concentrated in vacuo. Purification on a prepackedcolumn of silica gel (Isolute® SPE Column, 10 g Si/70 mL) with methanol(0-1% gradient) in methylene chloride as the eluent afforded 0.186 g(43%) of a colourless oil.

¹H NMR (400 MHz, CDCl₃): δ 1.10-1.24 (m, 6H), 2.88-2.99 (m, 2H), 2.91and 2.95 (2s, 3H, rotamers), 3.33 (m, 1H), 3.58 (m, 1H), 3.95 (m, 1H),4.08-4.20 (m, 2H), 4.57 and 4.59 (2s, 2H, rotamers), 4.69 and 4.70 (2s,2H, rotamers), 6.77 and 6.87 (2d, 2H, rotamers), 7.07-7.38 (m, 7H).

(ii)(2S)-3-(4-{2-[Benzyl(methyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoicacid

To a solution of ethyl(2S)-3-(4-{2-[benzyl(methyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoate(0.155 g, 0.39 mmol) in THF (20 mL) was added aqeuous 0.10 M LiOH (10mL) and the reaction mixture was stirred overnight. After acidificationwith 5% HCl, the mixture was extracted with ethyl acetate (3×50 mL) andthe combined organic phase was washed with brine (50 mL), dried overanhydrous Na₂SO₄, and concentrated in vacuo to afford 0.139 g (97%) of acolourless oil.

¹H NMR (400 MHz, CDCl₃): δ 1.10-1.20 (m, 3H), 2.86-3.10 (m, 2H), 2.94and 2.97 (2s, 3H, rotamers), 3.38 (m, 1H), 3.61 (m, 1H), 4.01 (m, 1H),4.59 and 4.61 (2s, 2H, rotamers), 4.72 and 4.73 (2s, 2H, rotamers), 6.78and 6.87 (2d, 2H, rotamers), 7.10-7.40 (m, 7H), 8.97 (bs, 1H).

Example 5 (2S)-2-Ethoxy-3-[4-(2-{heptyl[(1-methylindol-2-yl)methyl]amino}-2-oxoethoxy)phenyl]propanoic acid (i)N-heptyl-N-[(1-methylindol-2-yl)methyl]amine

To a solution of 1-methylindole-2-carbaldehyde (1.59 g, 10.0 mmol) andheptylamine (1.49 mL, 10.0 mmol) in ethanol (50 mL) were added aceticacid (2.3 mL, 40 mmol) and sodium cyanoborohydride (0.75 g, 12.0 mmol)and the reaction mixture was stirred at room temperature overnight.Water (5 mL) was added and the mixture was concentrated in vacuo Theresidue was taken up in ethyl acetate (75 mL) and aqueous 1 M KOH (75mL) and the phases were separated. The aqueous layer was extracted withethyl acetate (2×75 mL) and the combined organic phase was washed withbrine (75 mL), dried over Na₂SO₄, and concentrated in vacuo.Purification on a column of silica gel (130 g) with ethyl acetate(17-33% gradient) in heptane as the eluent yielded 1.57 g (61%) of ayellow oil, which solidified upon standing.

¹H NMR (400 MHz, CDCl₃): δ 0.87-0.95 (m, 3H), 1.20-1.40 (m, 8H),1.46-1.60 (m, 2H), 2.70 (t, 3H), 3.78 (s, 3H), 3.94 (s, 2H), 6.39 (s,1H), 7.09 (m, 1H), 7.20 (m, 1H), 7.31 (d, 1H), 7.58 (d, 1H).

(ii) Ethyl (2S)-2-ethoxy-3-[4-(2-{heptyl[(1-methylindol-2-yl)methyl]amino}-2-oxoethoxy)phenyl]propanoate

To a solution of {4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic acid(0.889 g, 3.00 mmol) and N-heptyl-N-[(1-methylindol-2-yl)methyl]amine(0.814 g, 3.15 mmol) in methylene chloride (30 mL) were added DMAP(0.403 g, 3.30 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (0.633 g, 3.30 mmol) and the reaction mixture was stirredat room temperature for three days. The mixture was diluted withmethylene chloride (100 mL) and the organic phase was washed with 2 MHCl (3×100 mL), saturated aqueous NaHCO₃ (100 mL), and brine (100 mL),dried over Na₂SO₄, and concentrated in vacuo. Purification on a columnof silica gel (100 g) with methanol (0-5% gradient) in methylenechloride as the eluent yielded 0.71 g (43%) of a pale yellow oil.

¹H NMR (400 MHz, CDCl₃): δ 0.82-0.93 (m, 3H), 1.18 (t, 3H), 1.14-1.36(m, 11H), 1.47-1.62 (m, 2H), 2.91-3.03 (m, 2H), 3.20-3.29 and 3.30-3.47(2m, 3H, rotamers), 3.58 (s, 3H), 3.61 (m, 1H), 3.98 (m, 1H), 4.18 (q,2H), 4.73 (s, 2H), 4.86 (s, 2H), 6.44 (s, 1H), 6.87 (d, 2H), 7.06-7.34(m, 5H), 7.57 (d, 1H).

(iii) (2S)-2-Ethoxy-3-[4-(2-{heptyl[(1-methylindol-2-yl)methyl]amino}-2-oxoethoxy)phenyl]propanoic acid

To a solution of ethyl(2S)-2-ethoxy-3-[4-(2-{heptyl[(1-methylindol-2-yl)methyl]amino}-2-oxoethoxy)phenyl]propanoate(0.655 g, 1.22 mmol) in THF (60 mL) was added aqueous 0.10 M LiOH (30mL) and the reaction mixture was stirred at room temperature overnight.After acidification with 2 M HCl, the mixture was extracted with ethylacetate (3×75 mL) and the combined organic phase was washed with brine(75 mL), dried over Na₂SO₄, and concentrated in vacuo to afford 0.61 g(95%) of a pale yellow oil.

¹H NMR (400 MHz, CDCl₃): δ 0.80-0.93 (m, 3H), 1.13-1.34 (m, 11H),1.46-1.62 (m, 2H), 2.97 and 3.10 (AB part of ABX system, 2H), 3.19-3.29and 3.38-3.55 (2m, 3H, rotamers), 3.58 (s, 3H), 3.59 (m, 1H), 4.07 (m,1H), 4.73 (s, 2H), 4.86 (s, 2H), 6.43 (s, 1H), 6.88 (d, 2H), 7.05-7.33(m, 5H), 7.56 (d, 1H).

Example 6(2S)-3-(4-{2-[(2,3-Dimethoxybenzyl)(heptyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoicacid (i) N-Heptyl-2,3-dimethoxybenzamide

To a solution of 2,3-dimethoxybenzoic acid (4.55 g, 25.0 mmol) inmethylene chloride (250 mL) were added heptylamine (2.78 g, 27.5 mmol)and DMAP (3.36 g, 27.5 mmol) followed by1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (5.27 g,27.5 mmol) and the reaction mixture was stirred at room temperatureovernight. The resulting solution was washed with 5% HCl (3×100 mL),saturated aqueous NaHCO₃ (100 mL), and brine (100 mL) and dried overMgSO₄. Concentration in vacuo afforded 6.81 g (98%) of a colourless oil.

¹H NMR (400 MHz, CDCl₃): δ 0.82-0.91 (m, 3H), 1.20-1.43 (m, 8H),1.53-1.66 (m, 2H), 3.40-3.48 (m, 2H), 3.87 (s, 3H), 3.88 (s, 3H), 7.02(dd, 1H), 7.13 (t, 1H), 7.67 (dd, 1H), 7.93 (bs, 1H).

(ii) N-(2,3-Dimethoxybenzyl)-N-heptylamine

N-Heptyl-2,3-dimethoxybenzamide (6.47 g, 23.2 mmol) was dissolved infreshly distilled THF (230 mL) and cooled in an ice bath under an argonatmosphere. Borane (29 mL of a 2 M solution of the dimethylsulfidecomplex in diethyl ether) was added and the ice bath was removed after15 minutes. The reaction mixture was refluxed overnight and was thenallowed to cool to room temperature. The reaction was quenched bycareful addition of 10% HCl (11 mL) and the mixture was stirred for fourhours and then concentrated in vacuo. The residue was taken up in ethylacetate (300 mL) and washed with aqueous 2 M K₂CO₃ (3×100 mL) and brine(100 mL), dried over Na₂SO₄, and concentrated in vacuo. Purification onsilica gel (160 g) with ethyl acetate (33-100% gradient) in heptane andfinally 5% ethanol in ethyl acetate as the eluent yielded 3.40 g (55%)of a light yellow oil.

¹H NMR (400 MHz, CDCl₃): δ 0.83-0.91 (m, 3H), 1.20-1.35 (m, 8H),1.42-1.54 (m, 2H), 2.54-2.61 (m, 2H), 3.79 (s, 2H), 3.85 (s, 3H), 3.86(s, 3H), 6.83 (d, 1H), 6.88 (d, 1H), 7.01 (t, 1H).

(iii) Ethyl(2S)-3-(4-{2-[(2,3-dimethoxybenzyl)(heptyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoate

To a solution of N-(2,3-dimethoxybenzyl)-N-heptylamine (1.46 g, 5.5mmol) and {4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic acid (1.48 g,5.0 mmol) in methylene chloride (50 mL) at 0° C. were addedN,N-diisopropylethylamine (2.0 mL, 11.5 mmol) and0-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(1.93 g, 6.0 mmol) and the reaction mixture was stirred at roomtemperature overnight and then concentrated in vacuo. The residue wastaken up in ethyl acetate (200 mL) and the organic phase was washed withsaturated aqueous NaHCO₃ (3×100 mL), 5% HCl (3×100 mL), and brine (100mL), dried over Na₂SO₄, and concentrated in vacuo. Purification onsilica gel (100 g) with methanol (0-2% gradient) in methylene chlorideas the eluent and collection of pure fractions yielded 1.57 g (58%) of apale yellow oil.

¹H NMR (400 MHz, CDCl₃): δ 0.82-0.90 (m, 3H), 1.11-1.30 (m, 14H),1.46-1.64 (m, 2H), 2.89-2.98 (m, 2H), 3.20-3.28 and 3.28-3.40 (2m, 3H,rotamers), 3.59 (m, 1H), 3.81, 3.82, 3.85 and 3.87 (4s, 6H, rotamers),3.95 (m, 1H), 4.11-4.20 (m, 2H), 4.59, 4.69, 4.70 and 4.72 (4s, 4H,rotamers), 6.69-6.91 (m, 4H), 6.95 and 7.02 (2t, 1H, rotamers), 7.11 and7.16 (2d, 2H, rotamers).

(iv)(2S)-3-(4-{2-[(2,3-Dimethoxybenzyl)(heptyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoicacid

To a solution of ethyl(2S)-3-(4-{2-[(2,3-dimethoxybenzyl)(heptyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoate(1.40 g, 2.55 mmol) in acetonitrile (100 mL) was added aqueous 0.10 MLiOH (50 mL) and the reaction mixture was stirred at room temperatureovernight. The solvent volume was reduced in vacuo and the remainingaqueous phase was acidified with 5% HCl and extracted with ethyl acetate(3×100 mL). The combined organic phase was washed with brine (75 mL),dried over Na₂SO₄, and concentrated in vacuo to afford 1.29 g (98%) of apale yellow oil.

¹H NMR (400 MHz, CDCl₃): δ 0.81-4.91 (m, 3H), 1.13-1.32 (m, 1H),1.46-1.64 (m, 2H), 2.94 (m, 1H), 3.07 (m, 1H), 3.25 and 3.34 (2m, 2H,rotamers), 3.44 (m, 1H), 3.59 (m, 1H), 3.82 (s, 3H), 3.86 and 3.88 (2s,3H, rotamers), 4.03 (m, 1H), 4.60, 4.70, 4.72 and 4.74 (4s, 4H,rotamers), 6.70-6.92 (m, 4H), 6.96 and 7.03 (2t, 1H, rotamers), 7.12 and7.17 (2d, 2H, rotamers).

Example 7(2S)-3-(4-{2-[Butyl(2,3-dimethoxybenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoicacid (i) N-Butyl-2,3-dimethoxybenzamide

To a solution of 2,3-dimethoxybenzoic acid (4.55 g, 25.0 mmol) inmetylene chloride (250 mL) were added butylamine (2.01 g, 27.5 mmol) andDMAP (3.36 g, 21.5 mmol) followed by1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (5.27 g,27.5 mmol) and the reaction mixture was stirred at room temperatureovernight. The resulting solution was washed with 5% HCl (3×100 mL),saturated aqueous NaHCO₃ (100 mL), and brine (100 mL) and dried overMgSO₄. Concentration in vacuo afforded 5.59 g (94%) of a colourless oil.

¹H NMR (400 MHz, CDCl₃): δ 0.94 (t, 3H), 1.35-1.47 (m, 2H), 1.53-1.63(m, 2H), 3.40-3.48 (m, 2H), 3.86 (s, 3H), 3.87 (s, 3H), 7.00 (dd, 1H),7.11 (t, 1H), 7.66 (dd, 1H), 7.92 (bs, 1H).

(ii) N-Butyl-N-(2,3-dimethoxybenzyl)amine

N-Butyl-2,3-dimethoxybenzamide (5.37 g, 22.6 mmol) was dissolved infreshly distilled THF (230 mL) and cooled in an ice bath under an argonatmosphere. Borane (28 mL of a 2 M solution of the dimethylsulfidecomplex in diethyl ether) was added and the ice bath was removed after15 minutes. The reaction mixture was refluxed overnight and was thenallowed to cool to room temperature. The reaction was quenched bycareful addition of 10% HCl (11 mL) and the mixture was stirred for fourhours and then concentrated in vacuo. The residue was taken up in ethylacetate (300 mL) and washed with aqueous 2 M K₂CO₃ (3×100 mL) and brine(100 mL), dried over Na₂SO₄, and concentrated in vacuo. Purification onsilica gel (160 g) with ethyl acetate (33-100% gradient) in heptane andfinally 5% ethanol in ethyl acetate as the eluent yielded-2.74 g (54%)of a light yellow oil.

¹H NMR (400 MHz, CDCl₃): δ 0.89 (t, 3H), 1.26-1.40 (m, 2H), 1.42-1.53(m, 2H), 2.56-2.63 (m, 214), 3.79 (s, 2H), 3.85 (s, 3H), 3.86 (s, 3H),6.83 (dd, 1H), 6.89 (dd, 1H), 7.01 (t, 1H).

(iii) Ethyl(2S)-3-(4-{2-[butyl(2,3-dimethoxybenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoate

To a solution of N-butyl-N-(2,3-dimethoxybenzyl)amine (1.23 g, 5.5 mmol)and {4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic acid (1.48 g, 5.0mmol) in methylene chloride (50 mL) at 0° C. were addedN}N-diisopropylethylamine (2.0 mL, 11.5 mmol) followed by0-(benzotriazol-1-yl)-N,N,N′,′-tetramethyluronium tetrafluoroborate(1.93 g, 6.0 mmol) and the reaction mixture was stirred overnight andthen concentrated in vacuo. The residue was taken up in ethyl acetate(200 mL) and the organic phase was washed with saturated aqueous NaHCO₃(3×100 mL), 5% HCl (3×100 mL), and brine (100 mL), dried over Na₂SO₄,and concentrated in vacuo. Purification on silica gel (120 g) withmethanol (0-2% gradient) in methylene chloride as the eluent andcollection of pure fractions afforded 1.07 g (43%) of a pale yellow oil.

¹H NMR (400 MHz, CDCl₃): δ 0.84-0.94 (m, 3H), 1.12-1.19 (m, 3H),1.19-1.35 (m, 5H), 1.46-1.64 (m, 2H), 2.88-3.00 (m, 2H), 3.21-3.29 and3.29-3.40 (2m, 3H, rotamers), 3.59 (m, 1H), 3.82, 3.82, 3.86 and 3.88(4s, 6H, rotamers), 3.96 (m, 1H), 4.11-4.21 (m, 2H), 4.60, 4.70, 4.71and 4.73 (4s, 4H, rotamers), 6.69-6.92 (m, 4H), 6.96 and 7.03 (2t, 1H,rotamers), 7.12 and 7.16 (2d, 2H, rotamers).

(iv)(2S)-3-(4-{2-[Butyl(2,3-dimethoxybenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoicacid

To a solution of ethyl(2S)-3-(4-{2-[(2,3-dimethoxybenzyl)(butyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoate(1.02 g, 2.0 mmol) in acetonitrile (80 mL) was added aqueous 0.10 M LiOH(40 mL) and the reaction mixture was stirred at room temperatureovernight. The solvent volume was reduced in vacuo and the remainingaqueous phase was acidified with 5% HCl and extracted with ethyl acetate(3×100 mL). The combined organic phase was washed with brine (75 mL),dried over Na₂SO₄, and concentrated in vacuo to afford 0.96 g (98%) of alight yellow oil.

¹H NMR (400 MHz, CDCl₃): δ 0.84-0.94 (m, 3H), 1.12-1.20 (m, 3H),1.20-1.36 (m, 2H), 1.45-1.64 (m, 2H), 2.94 (m, 1H), 3.06 (m, 1H), 3.26and 3.35 (2m, 2H, rotamers), 3.43 (m, 1H), 3.59 (m, 1H), 3.82 and 3.82(2s, 3H, rotamers), 3.86 and 3.88 (2s, 3H, rotamers), 4.03 (m, 1H),4.60, 4.70, 4.72 and 4.74 (4s, 4H, rotamers), 6.70-6.92 (m, 4H), 6.96and 7.03 (2t, 1H, rotamers), 7.12 and 7.17 (2d, 2H, rotamers).

Example 8(2S)-3-(4-{2-[(4-Chlorobenzyl)(4-isopropylbenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoicacid (i) N-(4-Chlorobenzyl)-N-(4-isopropylbenzyl)amine

To a solution of 4-chlorobenzyl amine (2.83 g, 20.0 mmol) and4-isopropylbenzaldehyde (2.96 g, 20.0 mmol) in methanol (100 mL) wereadded acetic acid (4.6 mL, 80 mmol) and sodium cyanoborohydride (1.51 g,24.0 mmol) and the solution was stirred at room temperature for threedays. Water (5 mL) was added and the mixture was concentrated in vacuo.The residue was taken up in ethyl acetate (100 mL) and aqueous 1 M KOH(100 mL) and the phases were separated. The aqueous phase was extractedwith ethyl acetate (2×100 mL) and the combined organic phase was washedwith brine (100 mL), dried over Na₂SO₄, and concentrated in vacuo toafford 5.80 g of crude product as a white semicrystalline oil. Theproduct was used in the subsequent reaction step without furtherpurification.

¹H NMR (400 MHz, CDCl₃): δ 1.22 (d, 6H), 2.88 (sep, 1H), 3.84 (s, 4H),5.72 (bs, 1H), 7.22 (d, 2H), 7.28 (d, 2H), 7.31 (bs, 4H).

(ii) Ethyl(2S)-3-(4-{2-[(4-chlorobenzyl)(4-isopropylbenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoate

To a solution of N-(4-chlorobenzyl)-N-(4-isopropylbenzyl)amine (1.64 g,6.0 mmol) in methylene chloride (50 mL) at 0° C. were added{4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic acid (1.48 g, 5.0 mmol)and N,N-diisopropylethylamine (2.0 mL, 11.5 mmol) followed byO-(benzotriazol-1-yl)-N,N,N′,′-tetramethyluronium tetrafluoroborate(1.93 g, 6.0 mmol) and the reaction mixture was stirred overnight. Themixture was diluted with methylene chloride (100 mL) and the organicphase was washes with 2 M HCl (3×75 mL), saturated aqueous NaHCO₃ (2×75mL, some emulsions), and brine (75 mL), dried over Na₂SO₄, andconcentrated in vacuo. Twice repeated purification on silica gel withmethanol (0-5% gradient) in methylene chloride as the eluent andcollection of pure fractions afforded 1.28 g (46%) of a colourless oil.

¹H NMR (400 MHz, CDCl₃): δ 1.16 (t, 3H), 1.19-1.28 (m, 9H), 2.82-3.02(m, 3H), 3.35 (m, 1H), 3.61 (m, 1H), 3.97 (m, 1H), 4.17 (q, 2H), 4.49,4.50, 4.52 and 4.54 (4s, 4H, rotamers), 4.74 and 4.77 (2s, 2H,rotamers), 6.75-6.86 (m, 2H), 7.04-7.36 (m, 10H).

(iii)(2S)-3-(4-{2-[(4-Chlorobenzyl)(4-isopropylbenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoicacid

To a solution of ethyl(2S)-3-(4-{2-[(4-chlorobenzyl)(4-isopropylbenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoate(1.15 g, 2.1 mmol) in acetonitrile (100 mL) was added aqueous 0.10 MLiOH (52 mL) and the solution was stirred at room temperature overnight.After neutralisation with 5% HCl, the solvent volume was reduced invacuo and the remaining aqueous phase was acidified with 5% HCl andextracted with ethyl acetate (3×100 mL). The combined organic phase waswashed with brine (75 mL), dried over Na₂SO₄, and concentrated in vacuoto afford 1.02 g (93%) of a colourless oil.

¹H NMR (400 MHz, CDCl₃): δ 1.17 (t, 3H), 1.21-1.28 (m, 6H), 2.92 (m,1H), 2.95 and 3.07 (AB part of ABX system, 2H), 3.44 (m, 1H), 3.61 (m,1H), 4.04 (m, 1H), 4.49, 4.50, 4.53 and 4.55 (4s, 4H, rotamers), 4.75and 4.78 (2s, 2H, rotamers), 6.76.87 (m, 2H), 7.04-7.36 (m, 10H).

Example 9(2S)-3-(4-{2-[(Cyclohexylmethyl)(2,4-difluorobenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoicacid (i) N-(Cyclohexylmethyl)-N-(2,4-difluorobenzyl)amine

To a solution of 2,4-difluorobenzylamine (2.84 g, 20.0 mmol) andcyclohexanecarbaldehyde (2.60 mL, 20.0 mmol) in methanol (100 mL) wereadded acetic acid (4.6 mL, 80 mmol) and sodium cyanoborohydride (1.51 g,24.0 mmol) and the solution was stirred at room temperature for threedays. Water (10 mL) was added and the mixture was concentrated in vacuo.The residue was diluted with aqueous 1 M KOH (125 mL) and ethyl acetate(100 mL) and the phases were separated. The aqueous phase was extractedwith ethyl acetate (2×100 mL) and the combined organic phase was driedover Na₂SO₄ and concentrated in vacuo. Purification on a prepackedcolumn of silica gel (Isolute® SPE Column, 50 g Si/150 mL) with ethylacetate (33-100% gradient) in heptane as the eluent yielded 2.40 g (50%)of white solids.

¹H NMR (400 MHz, CDCl₃): δ 0.90-1.04 (m, 2H), 1.07-1.34 (m, 3H),1.61-1.85 (m, 6H), 2.72 (d, 2H), 4.19 (s, 2H), 6.90 (m, 1H), 6.97 (m,1H), 7.0 (bs, 1H), 7.63 (m, 1H).

(ii) Ethyl(2S)-3-(4-{2-[(cyclohexylmethyl)(2,4-difluorobenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoate

To a solution of N-(cyclohexylmethyl)-N-(2,4-difluorobenzyl)amine (0.574g, 2.00 mmol) and {4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic acid(0.593 g, 2.00 mmol) in methylene chloride (20 mL) were addedN,N-diisopropylethylamine (0.80 mL, 4.6 mmol) andO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(0.674 g, 2.10 mmol) and the reaction mixture was stirred at roomtemperature overnight. The mixture was diluted with methylene chloride(100 mL) and the organic phase was washed with 2 M HCl (3×75 mL),saturated aqueous NaHCO₃ (2×75 mL), and brine (75 mL), dried overNa₂SO₄, and concentrated in vacuo. Purification on a prepacked column ofsilica gel (Isolute® SPE Column, 20 g/70 mL) with methanol (0-2%gradient) in methylene chloride as the eluent yielded 0.59 g (57%) of acolourless oil.

¹H NMR (400 MHz, CDCl₃): δ 0.83-1.02 (m, 2H), 1.08-1.30 (m, 9H),1.51-1.82 (m, 6H), 2.88-3.00 (m, 2H), 3.10-3.22 (m, 2H), 3.35 (m, 1H),3.60 (m, 1H), 3.96 (m, 1H), 4.16 (q, 2H), 4.63 (s, 2H), 4.70 and 4.71(2s, 2H, rotamers), 6.72-6.90 (m, 4H), 7.05-7.18 and 7.18-7.29 (2m, 3H,rotamers).

(iii)(2S)-3-(4-{2-[(Cyclohexylmethyl)(2,4-difluorobenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoicacid

To a solution of ethyl(2S)-3-(4-{2-[(cyclohexylmethyl)(2,4-difluorobenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoate(0.297 g, 0.57 mmol) in acetonitrile (28 mL) was added aqueous 0.10 MLiOH (14 mL) and the solution was stirred at room temperature overnight.After neutralisation with 5% HCl, the solvent volume was reduced invacuo and the remaining aqueous phase was acidified with 5% HCl andextracted with ethyl acetate (3×100 mL). The combined organic phase waswashed with brine (100 mL), dried over Na₂SO₄, and concentrated in vacuoto afford 0.258 g (89%) of a colourless oil.

¹H NMR (400 MHz, CDCl₃): 0.80-1.00 (m, 2H), 1.03-1.30 (m, 6H), 1.48-1.80(m, 6H), 2.92 (m, 1H), 3.01 (m, 1H), 3.10-3.20 (m, 2H), 3.35 (m, 1H),3.60 (m, 1H), 3.99 (m, 1H), 4.62 (s, 2H), 4.72 (s, 2H), 6.70-6.88 (m,4H), 7.05-7.19 and 7.19-7.29 (2m, 3H, rotamers).

Example 10(2S)-2-Ethoxy-3-(4-{2-[ethyl(2-fluorobenzyl)amino]-2-oxoethoxy}phenyl)propanoicacid (i) Ethyl(2S)-2-ethoxy-3-(4-{2-[ethyl(2-fluorobenzyl)amino]-2-oxoethoxy}phenyl)propanoate

To a solution of N-ethyl-N-(2-fluorobenzyl)amine (0.843 g, 5.50 mmol)and {4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic acid (1.482 g, 5.00mmol) in methylene chloride (50 mL) were added N,N-diisopropylethylamine(2.00 mL, 11.5 mmol) andO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(1.93 g, 6.0 mmol) and the reaction mixture was stirred at roomtemperature overnight. The resulting solution was diluted with methylenechloride (50 mL) and the organic phase was washed with 2 M HCl (3×75mL), saturated aqueous NaHCO₃ (2×75 mL), and brine (75 mL), dried overNa₂SO₄, and concentrated in vacuo. Purification on a prepacked column ofsilica gel (Isolute® SPE Column, 70 g/150 mL) with methanol (0-2%gradient) in methylene chloride as the eluent yielded 1.90 g (88%) of acolourless oil.

¹H NMR (400 MHz, CDCl₃): δ 1.04-1.26 (m, 9H), 2.89-2.98 (m, 2H),3.27-3.44 (m, 3H), 3.59 (m, 1H), 3.95 (m, 1H), 4.10-4.20 (m, 2H), 4.64,4.67, 4.70, and 4.72 (4s, 4H, rotamers), 6.76 and 6.87 (2d, 2H,rotamers), 6.97-7.32 (m, 6H).

¹³C NMR (100 MHz, CDCl₃): δ 12.4, 13.9, 14.3, 15.1, 38.5, 41.0, 41.3(d), 41.7, 44.3 (d), 60.9, 66.3, 67.6, 67.9, 80.4, 114.5, 114.6, 115.3(d), 115.7 (d), 123.8 (d), 124.2 (d), 124.5 (m), 128.7, 128.7 129.1 (d),129.5 (d), 130.3-130.6 (m), 130.5, 130.6, 156.8, 156.9, 160.9 (d), 161.1(d), 168.0, 168.1, 172.6. (The number of peaks is larger than the numberof carbon atoms due to rotamers.)

(ii)(2S)-2-Ethoxy-3-(4-{2-[ethyl(2-fluorobenzyl)amino]-2-oxoethoxy}phenyl)propanoicacid

To a solution of ethyl(2S)-2-ethoxy-3-(4-{2-[ethyl(2-fluorobenzyl)amino]-2-oxoethoxy}phenyl)propanoate(0.980 g, 2.27 mmol) in acetonitrile (120 mL) was added aqueous 0.10 MLiOH (57 mL) and the reaction mixture was stirred at room temperatureovernight. After neutralisation with 5% HCl, the solvent volume wasreduced in vacuo and the remaining aqueous phase was acidified with 5%HCl and extracted with ethyl acetate (3×100 mL). The combined organicphase was washed brine (100 mL), dried over Na₂SO₄, and concentrated invacuo to afford 0.868 g (95%) of a pale yellow oil.

¹H NMR (400 MHz, CDCl₃): δ 1.05-1.28 (m, 6H), 2.87-2.99 (m, 1H),2.99-3.10 (m, 1H), 3.33-3.45 (m, 3H), 3.61 (m, 1H), 4.01 (m, 1H), 4.65,4.68, 4.72, and 4.73 (4s, 4H, rotamers), 6.77 and 6.87 (2d, 2H,rotamers), 6.96-7.33 (m, 6H), 9.04 (bs, 1H).

¹³C NMR (100 MHz, CDCl₃): δ 12.4, 13.9, 15.1, 38.0, 41.2, 41.4 (d),41.7, 44.4 (d), 66.7, 67.4, 67.7, 79.8, 114.6, 114.7, 115.3 (d), 115.7(d), 123.6 (d), 124.0 (d), 124.5 (m), 128.7, 129.2 (d), 129.6 (d),130.0-130.8 (m), 130.6, 130.7, 156.8, 156.9, 160.9 (d), 161.1 (d),168.4, 168.5, 175.6. (The number of peaks is larger than the number ofcarbon atoms due to rotamers.

Example 11(2S)-3-(4-{2-[[4-(benzyloxy)benzyl](butyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoicacid (i) Ethyl(2S)-3-(4-{2-[[4-(benzyloxy)benzyl](butyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoate

To a solution of N-[4-(benzyloxy)benzyl]-N-butylamine (3.59 g, 12.0mmol) and {4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic acid (2.96 g,10.0 mmol) in methylene chloride (100 mL) were addedN,N-diisopropylethylamine (4.00 mL, 23.0 mmol) andO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(3.85 g, 12.0 mmol) and the reaction mixture was stirred at roomtemperature overnight. The resulting solution was diluted with methylenechloride (100 mL) and the organic phase was washed with 5% HCl (3×75mL), saturated aqueous NaHCO₃ (2×75 mL), and brine (75 mL), dried overNa₂SO₄, and concentrated in vacuo. Purification on a prepacked column ofsilica gel (Isolute® SPE Column, 70 g/150m L) with methanol (0-1%gradient) in methylene chloride as the eluent and collection of purefractions yielded 1.80 g (33%) of a whitish oil.

¹H NMR (400 MHz, CDCl₃): δ 0.80-0.95 (m, 3H), 1.12-1.20 (m, 3H),1.20-1.35 (m, 5H), 1.44-1.61 (m, 2H), 2.88-3.02 (m, 2H), 3.19-3.28 and3.29-3.41 (2m, 3H, rotamers), 3.60 (m, 1H), 3.97 (m, 1H), 4.16 (q, 2H),4.54 and 4.55 (2s, 2H, rotamers), 4.66 and 4.72 (2s, 2H, rotamers), 5.50and 5.06 (2s, 2H, rotamers), 6.76-7.00 (m, 4H), 7.07-7.21 (m, 4H),7.28-7.47 (m, 5H).

(ii)(2S)-3-(4-{2-[[4-(benzyloxy)benzyl](butyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoicacid

To a solution of ethyl(2S)-3-(4-{2-[[4-(benzyloxy)benzyl](butyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoate(0.116 g, 0.21 mmol) in acetonitrile (10 mL) was added aqueous 0.10 MLiOH (5 mL) and the reaction mixture was stirred at room temperatureovernight. The solvent volume was reduced in vacuo and the remainingaqueous phase was diluted with water and aqueous 1 M KOH and washed withdiethyl ether (2×50 mL). The aqueous phase was acidified with 5% HCl andextracted with ethyl acetate (3×50 mL). The combined organic phase waswashed with brine (50 mL), dried over Na₂SO₄, and concentrated in vacuoto afford 0.070 g (63%) of a colourless oil.

¹H NMR (400 MHz, CDCl₃): δ0.83-0.95 (m, 3H), 1.10-1.20 (m, 3H),1.20-1.36 (m, 2H), 1.42-1.62 (m, 2H), 2.95 (m, 1H), 3.05 (m, 1H),3.19-3.29 and 3.30-3.46 (2m, 3H, rotamers), 3.61 (m, 1H), 4.02 (m, 1H),4.54 and 4.56 (2s, 2H, rotamers), 4.68 and 4.74 (2s, 2H, rotamers), 5.04and 5.06 (2s, 2H, rotamers), 6.76-7.00 (m, 4H), 7.09-7.22 (m, 4H),7.28-7.47 (m, 5H).

Example 12(2S)-3-(4-{2-[bis(4-Chlorobenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoicacid (i) Ethyl(2S)-3-(4-{2-[bis(4-chlorobenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoate

To a suspension of N,N-bis(4-chlorobenzyl)amine (0.958 g, 3.60-mmol) inmethylene chloride (30 mL) were added{4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic acid (0.889 g, 3.00mmol) and N,N-diisopropylethylamine (1.20 mL, 6.9 mmol) followed byO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(1.01 g, 3.15 mmol) and the reaction mixture was stirred at roomtemperature overnight. The resulting solution was diluted with methylenechloride (220 mL) and the organic phase was washed with 2 M HCl (3×50mL), saturated aqueous NaHCO₃ (2×50 mL), and brine (50 mL), dried overNa₂SO₄, and concentrated in vacuo. Purification on a prepacked column ofsilica gel (Isolute® SPE Column, 50 g/150 mL) with methanol (0-2%gradient) in methylene chloride as the eluent yielded 1.02 g (62%) of anoil, which solidified upon standing to give white solids.

¹H NMR (400 MHz, CDCl₃): δ 1.17 (t, 3H), 1.23 (t, 3H), 2.90-3.00 (m,2H), 3.36 (m, 1H), 3.61 (m, 1H), 3.97 (m, 1H), 4.17 (q, 2H), 4.50 (s,2H), 4.76 (s, 4H), 6.80 (d, 2H), 7.03-7.11 (m, 4H), 7.15 (d, 2H),7.21-7.35 (m, 4H).

¹³C NMR (100 MHz, CDCl₃): δ 14.4, 15.2, 38.5, 47.6, 49.2, 61.0, 66.3,68.1, 80.3, 114.5, 128.5, 129.0, 129.3, 129.9, 130.7, 133.7, 133.9,134.5, 135.0, 156.6, 168.7, 172.5.

(ii)(2S)-3-(4-{2-[bis(4-Chlorobenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoicacid

To a solution of ethyl(2S)-3-(4-{2-[bis(4-chlorobenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoate(0.597 g, 1.10 mmol) in acetonitrile (54 mL) was added aqueous 0.10 MLiOH (27 mL) and the reaction mixture was stirred at room temperatureovernight. The solvent volume was reduced in vacuo and the remainingaqueous phase was diluted with water and aqueous 1 M KOH (to a totalvolume of 400 mL, pH˜9) and washed with diethyl ether (2×100 mL). (Theextraction process was complicated by the formation of emulsions.) Theaqueous phase was acidified with 2 M HCl and extracted with ethylacetate (4×75 mL). The combined organic phase was washed with brine (100mL), dried over Na₂SO₄, and concentrated in vacuo to afford 0.475 g(84%) of a whitish oil. ¹H NMR (400 MHz, CDCl₃): δ 1.19 (t, 3H), 2.97and 3.08 (AB part of ABX system, 2H), 3.47 (m, 1H), 3.61 (m, 1H), 4.06(m, 1H), 4.50 (s, 4H), 4.76 (s, 2H), 6.80 (d, 2H), 7.04-7.12 (m, 4H),7.15 (d, 2H), 7.25 (d, 2H), 7.32 (d, 2H).

¹³C NMR (100 MHz, CDCl₃): δ 15.2, 37.7, 47.7, 49.3, 67.0, 68.0, 79.8,114.7, 128.5, 129.0, 129.3, 129.9, 130.0, 130.9, 133.7, 133.9, 134.4,135.0, 156.8, 168.8, 174.1.

Example 13(2S)-3-(4-{2-[(4-tert-Butylbenzyl)(4-chlorobenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoicacid (i) N-(4-tert-Butylbenzyl)-N-(4-chlorobenzyl)amine

To a solution of 4-tert-butylbenzaldehyde (3.24 g, 20.0 mmol) and4-chlorobenzylamine (2.43 mL, 20.0 mmol) in methanol (100 mL) were addedacetic acid (4.6 mL, 80 mmol) and sodium cyanoborohydride (1.51 g, 24.0mmol) and the reaction mixture was stirred at room temperatureovernight. Water (10 mL) was added and the mixture was concentrated invacuo. The residue was taken up in ethyl acetate (50 mL) and aqueous 1 MKOH (50 mL) and the phases were separated. The aqueous phase wasextracted with ethyl acetate (2×50 mL) and the combined organic phasewas dried over Na₂SO₄, and concentrated in vacuo. Purification on aprepacked column of silica gel (Isolute® SPE Column, 70 g/150 mL) withethyl acetate (33-100% gradient) in heptane as the eluent yielded 4.31 g(75%) of white solids.

¹H NMR (400 MHz, CDCl₃): δ 1.28 (s, 9H), 3.90 (s, 2H), 3.92 (s, 2H),6.15 (bs, 1H), 7.28-7.33 (m, 6H), 7.40 (d, 2H).

¹³C NMR (100 MHz, CDCl₃): δ 31.3, 34.8, 50.1, 50.8, 126.3, 129.0, 129.4,129.5, 130.9, 131.2, 135.3, 152.6.

(ii) Ethyl(2S)-3-(4-{2-[(4-tert-butylbenzyl)(4-chlorobenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoate

To a solution of {4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic acid(0.889 g, 3.00 mmol) in methylene chloride (30 mL) were addedN-(4-tert-butylbenzyl)-N-(4-chlorobenzyl)amine (1.04 g, 3.60 mmol),N,N-diisopropylethylamine (1.20 mL, 6.9 mmol) andO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(1.01 g, 3.15 mmol) and the reaction mixture was stirred at roomtemperature overnight. The resulting solution was diluted with methylenechloride (220 mL) and the organic phase was washed with 2 M HCl (3×50mL), saturated aqueous NaHCO₃ (2×50 mL), and brine (50 mL), dried overNa₂SO₄, and concentrated in vacuo. Twice repeated purification onprepacked columns of silica gel (Isolute® SPE Column, 50 g/150 mL) withmethanol (0-2% gradient) in methylene chloride as the eluent andcollection of pure fractions yielded 0.459 g (27%) of a whitish oil.

¹H NMR (400 MHz, CDCl₃): δ 1.16 (t, 3H), 1.23 (t, 3H), 1.31 and 1.33(2s, 9H, rotamers), 2.88-3.02 (m, 2H), 3.35 (m, 1H), 3.61 (m, 1H), 3.97(m, 1H), 4.17 (q, 2H), 4.49 and 4.50 (2s, 2H, rotamers), 4.53 and 4.55(2s, 2H, rotamers), 4.74 and 4.77 (2s, 2H, rotamers), 6.76-6.86 (m, 2H),7.09 (d, 4H), 7.14 (d, 2H), 7.24, 7.31, and 7.37 (3d, 4H, rotamers).

³C NMR (100 MHz, CDCl₃): δ 14.3, 15.2, 31.4, 34.7, 38.6, 47.8, 48.0,49.1, 49.4, 60.9, 66.3, 67.7, 68.1, 80.4, 114.6, 114.6, 125.7, 126.0,126.7, 128.3, 128.4, 128.8, 129.1, 129.9, 130.6, 130.6, 132.8, 133.4,133.7, 134.8, 135.5, 150.8, 151.2, 156.7, 168.5, 168.6, 172.6. (Thenumber of peaks is larger than the number of carbon atoms due torotamers.)

(iii)(2S)-3-(4-{2-[(4-tert-Butylbenzyl)(4-chlorobenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoicacid

To a solution of ethyl(2S)-3-(4-{2-[(4-tert-butylbenzyl)(4-chlorobenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoate(0.400 g, 0.71 mmol) in acetonitrile (36 mL) was added aqueous 0.10 MLiOH (18 mL) and the reaction mixture was stirred at room temperatureovernight. After acidification with 2 M HCl, the solvent volume wasreduced in vacuo and the mixture was extracted with ethyl acetate (3×75mL). The combined organic phase was washed with brine (75 mL), driedover Na₂SO₄, and concentrated in vacuo to afford 0.375 g (99%) of awhitish oil.

¹H NMR (400 MHz, CDCl₃): δ 1.18 (t, 3H), 1.31 and 1.33 (2s, 9H,rotamers), 2.96 and 3.07 (AB part of ABX system, 2H), 3.44 (m, 1H), 3.61(m, 1H), 4.04 (m, 1H), 4.49 and 4.50 (2s, 2H, rotamers), 4.53 and 4.55(2S, 2H, rotamers), 4.75 and 4.78 (2s, 2H, rotamers), 6.76-6.87 (m, 2H),7.09 (d, 4H), 7.15 (d, 2H), 7.24, 7.31, and 7.37 (3d, 4H, rotamers).

¹³C NMR (100 MHz, CDCl₃): δ 15.2, 31.5, 34.7, 37.9, 47.8, 48.0, 49.1,49.5, 67.0, 67.6, 68.0, 79.8, 114.7, 114.8, 125.7, 126.1, 126.8, 128.3,128.4, 128.9, 129.2, 129.9, 130.0, 130.8, 132.7, 133.4, 133.5, 133.7,134.8, 135.4, 150.8, 151.2, 156.9, 168.6, 168.8, 174.7. (The number ofpeaks is larger than the number of carbon atoms due to rotamers.)

Example 14 (2S)-3-[4-(2-{(4-Chlorobenzyl)[4-(trifluoromethyl)benzyl]amino}-2-oxoethoxy)phenyl]-2-ethoxypropanoicacid (i) Ethyl(2S)-3-[4-(2-{(4-chlorobenzyl)[4-(trifluoromethyl)benzyl]amino}-2-oxoethoxy)phenyl]-2-ethoxypropanoate

To a suspension of N-(4-chlorobenzyl)-N-[4-(trifluoromethyl)benzyl]amine(0.989 g, 3.30 mmol) and{4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic acid (0.889 g, 3.00mmol) in methylene chloride (60 mL) were added N,N-diisopropylethylamine(1.20 mL, 6.9 mmol) andO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(1.01 g, 3.1 mmol) and the reaction mixture was stirred at roomtemperature overnight. The resulting solution was diluted with methylenechloride (190 mL) and the organic phase was washed with 2 M HCl (3×50mL), saturated aqueous NaHCO₃ (2×50 mL), and brine (50 mL), dried overNa₂SO₄, and concentrated in vacuo. Twice repeated purification onprepacked columns of silica gel (Isolute® SPE Column, 70 g/150 mL) withmethanol (0-2% gradient) in methylene chloride as the eluent yielded1.02 g (59%) of a colourless oil.

¹H NMR (400 MHz, CDCl₃): δ 1.16 (t, 3H), 1.22 (t, 3H), 2.90-3.00 (m,2H), 3.35 (m, 1H), 3.60 (m, 1H), 3.97 (m, 1H), 4.17 (q, 2H), 4.52 (s,2H), 4.59 (s, 2H), 4.76 and 4.78 (2s, 2H, rotamers), 6.77 and 6.81 (2d,2H, rotamers), 7.03-7.11 (m, 2H), 7.11-7.19 (m, 2H), 7.20-7.36 (m, 4H),7.53 and 7.60 (2d, 2H rotamers).

¹³C NMR (100 MHz, CDCl₃): δ 14.4, 15.2, 38.5, 47.8, 47.9, 49.5, 61.0,66.3, 68.1, 68.2, 80.3, 114.5, 114.5, 125.7 (m), 126.0 (m), 127.4,128.5, 128.6, 129.0, 129.3, 129.6-131.2 (m), 129.9, 130.8, 130.8, 133.8,134.0, 134.3, 134.9, 140.2, 140.6, 156.5, 168.8, 172.5. (The number ofpeaks is larger than the number of carbon atoms due to rotamers.Trifluorinated carbon not reported)

(ii)(2S)-3-[4-(2-{(4-Chlorobenzyl)[4-(trifluoromethyl)benzyl]amino}-2-oxoethoxy)phenyl]-2-ethoxypropanoic acid To a solution of ethyl(2S)-3-[4-(2-{(4-chlorobenzyl)[4-(trifluoromethyl)benzyl]amino}-2-oxoethoxy)phenyl]-2-ethoxypropanoat(0.482 g, 0.83 mmol) in acetonitrile (42 mL) was added aqueous 0.10 MLiOH (21 mL) and the solution was stirred at room temperature overnight.After acidification with 2 M HCl, the solvent volume was reduced invacuo and the mixture was extracted with ethyl acetate (3×75 mL). Thecombined organic phase was washed with brine (75 mL), dried over Na₂SO₄,and concentrated in vacuo to afford 0.407 g (89%) of a colourless oil.

¹H N (400 MHz, CDCl₃): δ 1.18 (t, 3H), 2.97 and 3.07 (AB part of ABXsystem, 2H), 3.44 (m, 1H), 3.62 (m, 1H), 4.04 (m, 1H), 4.53 (s, 2H),4.60 (s, 2H), 4.77 and 4.79 (2s, 2H, rotamers), 6.77 and 6.81 (2d, 2H,rotamers), 7.04-7.12 (m, 2H), 7.12-7.20 (m, 2H), 7.21-7.37 (m, 4H), 7.53and 7.60 (2d, 2H, rotamers).

¹³C NMR (100 MHz, CDCl₃): δ 15.2, 37.9, 47.9, 48.0, 49.6, 66.9, 68.0,68.1, 79.7, 114.6, 114.6, 125.7 (m), 126.0 (m), 127.3, 128.5, 128.6,129.0, 129.3, 129.9, 130.2, 130.9, 133.8, 134.0, 134.2, 134.8, 140.1,140.5, 156.6, 169.0, 175.2. (The number of peaks is larger than thenumber of carbon atoms due to rotamers. Trifluorinated carbon andquarternary carbon α to the trifluoromethyl group not reported.)

Example 15(2S)-3-[4-(2-{bis[4-(Trifluoromethyl)benzyl]amino}-2-oxoethoxy)phenyl]-2-ethoxypropanoicacid (i) Ethyl(2S)-3-[4-(2-1{bis[4-(trifluoromethyl)benzyl]amino}-2-oxoethoxy)phenyl]-2-ethoxy-propanoate

To a solution of N,N-bis[4-(trifluoromethyl)benzyl]amine (0.733 g, 2.20mmol) and {4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic acid (0.593g, 2.00 mmol) in methylene chloride (20 mL) were addedN,N-diisopropylethylamine (0.80 mL, 4.6 mmol) andO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(0.674 g, 2.10 mmol) and the reaction mixture was stirred at roomtemperature for 4 h. The resulting solution was diluted with methylenechloride (130 mL) and the organic phase was washed with 5% HCl (3×75mL), saturated aqueous NaHCO₃ (2×75 mL), and brine (75 mL), dried overNa₂SO₄, and concentrated in vacuo. Purification on a prepacked column ofsilica gel (Isolute® SPE Column, 70 g/150 mL) with methanol (0-1%gradient) in methylene chloride as the eluent yielded 0.91 g (74%) of awhitish oil.

¹H NMR (400 MHz, CDCl₃): δ 1.15 (t, 3H), 1.22 (t, 3H), 2.90-3.00 (m,1H), 3.35 (m, 1H), 3.60 (m, 1H), 3.96 (m, 1H), 4.16 (q, 2H), 4.61 (s,2H), 4.63 (s, 2H), 4.79 (s, 2H), 6.78 (d, 2H), 7.15 (d, 2H), 7.26 (m,2H), 7.53 (d, 2H), 7.60 (d, 2H).

¹³C NMR (100 MHz, CDCl₃): δ 14.3, 15.2, 38.5, 48.2, 49.8, 60.9, 66.3,68.2, 80.3, 114.5, 125.8 (m), 126.1 (m), 127.4, 128.6, 130.1 (q), 130.8,130.9, 140.1, 140.5, 156.5, 169.0, 172.5. (Trifluorinated carbon notreported.)

(ii)(2S)-3-[4-(2-{bis[4-(trifluoromethyl)benzyl]amino}-2-oxoethoxy)phenyl]-2-ethoxy-propanoicacid

To a solution of ethyl(2S)-3-[4-(2-{bis[4-(trifluoromethyl)benzyl]amino}-2-oxoethoxy)phenyl]-2-ethoxypropanoate (0.662 g, 1.1 mmol) in acetonitrile (54 mL)was added aqueous 0.10 M LiOH (27 mL) and the solution was stirred atroom temperature overnight. The solvent volume was reduced in vacuo andthe remaining aqueous phase was diluted with water and aqueous 0.10 MLiOH (to a total volume of 300 mL, pH˜12) and washed with diethyl ether(2×100 mL). (The extraction process was complicated by the formation ofemulsions.) The aqueous phase was acidified with 2 M HCl and extractedwith ethyl acetate (3×100 mL). The combined organic phase was washedwith brine (100 mL), dried over Na₂SO₄, and concentrated in vacuo toafford 0.292 g (46%) of a colourless oil.

¹H NMR (400 MHz, CDCl₃): δ 1.18 (t, 3H), 2.97 and 3.07 (AB part of ABXsystem, 2H), 3.46 (m, 1H), 3.62 (m, 1H), 4.05 (dd, 1H), 4.62 (s, 2H),4.64 (s, 2H), 4.80 (s, 2H), 6.79 (d, 2H), 7.16 (d, 2H), 7.22-7.31 (m,4H), 7.53 (d, 2H), 7.60 (d, 2H).

³C NMR (100 MHz, CDCl₃): δ 15.2, 37.8, 48.3, 49.9, 66.9, 68.1, 79.7,114.6, 125.8 (m), 126.1 (m), 127.4, 128.6, 130.5 (q), 130.2, 130.9,140.0, 140.4, 156.6, 169.1, 174.9. (Trifluorinated carbon not reported.)

Example 16(2S)-3-(4-{2-[Benzyl(ethyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoicacid (i) Ethyl(2S)-3-(4-{2-[benzyl(ethyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoate

To a solution of {4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic acid(0.296 g, 1.00 mmol) and N-benzyl-N-ethylamine (0.149 g, 1.10 mmol) inmethylene chloride (10 mL) were added N,N-diisopropylethylamine (0.40mL, 2.3 mmol) and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (0.353 g, 1.10 mmol) and the reaction mixture wasstirred at room temperature for three days. The resulting solution wasdiluted with methylene chloride (90 mL) and the organic phase was washedwith 2 M HCl (3×50 mL), saturated aqueous NaHCO₃ (2×50 mL), and brine(50 mL), dried over Na₂SO₄, and concentrated in vacuo. Purification on aprepacked column of silica gel (Isolute® SPE Column, 70 g/150 mL) withmethanol (0-1% gradient) in methylene chloride as the eluent andcollection of pure fractions yielded 0.129 g (31%) of a whitish oil.

¹H NMR (400 MHz, CDCl₃): δ 1.06-1.32 (m, 9H), 2.87-3.02 (m, 2H),3.26-3.48 (m, 3H), 3.60 (m, 1H), 3.96 (m, 1H), 4.10-4.21 (m, 2H), 4.61and 4.62 (2s, 2H, rotamers), 4.66 and 4.74 (2s, 2H, rotamers), 6.78 and6.89 (2d, 2H, rotamers), 7.08-7.40 (m, 7H).

(ii)(2S)-3-(4-{2-[Benzyl(ethyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoicacid

To a solution of ethyl(2S)-3-(4-{2-[benzyl(ethyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoate(0.112 g, 0.27 mmol) in acetonitrile (14 mL) was added aqueous 0.10 MLiOH (7 mL) and the reaction mixture was stirred at room temperatureovernight. After neutralisation with 5% HCl, the solvent volume wasreduced in vacuo and the mixture was extracted with ethyl acetate (3×50mL). The combined organic phase was washed with brine (50 mL), driedover Na₂SO₄, and concentrated in vacuo to afford 0.096 g (92%) of acolourless oil.

¹H NMR (400 MHz, CDCl₃): δ 1.05-1.21 (m, 6H), 2.85-3.10 (m, 2H),3.28-3.48 (m, 3H), 3.61 (m, 1H), 4.01 (m, 1H), 4.61 and 4.62 (2s, 2H,rotamers), 4.67 and 4.75 (2s, 2H, rotamers), 6.76 and 6.88 (2d, 2H,rotamers), 7.08-7.38 (m, 7H), 8.78 (bs, 1H).

Example 17(2S)-3-(4-{2-[(4-tert-Butylbenzyl)(ethyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoicacid (i) Ethyl(2S)-3-(4-{2-[(4-tert-butylbenzyl)(ethyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoate

To a solution of N-(4-tert-butylbenzyl)-N-ethylamine (0.383 g, 2.00mmol) and {4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic acid (0.593g, 2.00 mmol) in methylene chloride (20 mL) were addedN,N-diisopropylethylamine (0.80 mL, 4.6 mmol) andO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(0.706 g, 2.20 mmol) and the reaction mixture was stirred at roomtemperature overnight. The resulting solution was diluted with methylenechloride (40 mL) and the organic phase was washed with 5% HCl (50 mL),saturated aqueous NaHCO₃ (50 mL), and brine (50 mL), dried over Na₂SO₄,and concentrated in vacuo. Purification on a prepacked column of silicagel (Isolute® SPE Column, 50 g/150 mL) with methylene chloride/ethylacetate 10:1 as the eluent yielded 0.54 g (58%) of a colourless oil. ¹HNMR (500 MHz, CDCl₃): δ 1.07-1.25 (m, 9H), 1.30 and 1.32 (2s, 9H,rotamers), 2.88-3.00 (m, 2H), 3.28-3.40 and 3.40-3.48 (2m, 3H,rotamers), 3.60 (m, 1H), 3.96 (m, 1H), 4.12-4.20 (m, 2H), 4.57 and 4.59(2s, 2H, rotamers), 4.66 and 4.73 (2s, 2H, rotamers), 6.78 and 6.89 (2d,2H, rotamers), 7.09-7.20 (m, 4H), 7.31 and 7.36 (2d, 2H, rotamers).

(ii)(2S)-3-(4-{2-[(4-tert-Butylbenzyl)(ethyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoicacid

To a solution of ethyl(2S)-3-(4-{2-[(4-tert-butylbenzyl)(ethyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoate(0.520 g, 1.11 mmol) in THF (50 mL) was added aqueous 0.10 M LiOH (25mL) and the solution was stirred at room temperature overnight. Afterneutralisation with 5% HCl, the solvent volume was reduced in vacuo andthe remaining aqueous phase was acidified with 5% HCl and extracted withethyl acetate (2×50 mL). The combined organic phase was washed withbrine (50 mL), dried over Na₂SO₄, and concentrated in vacuo to afforded0.42 g (86%) of a colourless oil.

¹H NMR (500 MHz, CDCl₃): δ 1.08-1.22 (m, 6H), 1.30 and 1.32 (2s, 9H,rotamers), 2.94 (m, 1H), 3.07 (m, 1H), 3.30-3.50 (m, 3H), 3.59 (m, 1H),4.04 (m, 1H), 4.57 and 4.59 (2s, 2H, rotamers), 4.67 and 4.74 (2s, 2H,rotamers), 6.79 and 6.89 (2d, 2H, rotamers), 7.09-7.21 (m, 4H), 7.31 and7.36 (2d, 2H, rotamers).

The following examples were prepared in a similar manner.

Example 18 (2S)-3-(4-{2-[(4-Cyclohexylbutyl)(2,4-difluorobenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acidExample 19(2S)-3-(4-{2-[(2,4-Difluorobenzyl)(4-biphenylylethyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoicacid Example 20(2S)-3-(4-{3-[(2,4-Difluorobenzyl)(heptyl)amino]-3-oxopropyl}phenyl)-2-ethoxypropanoicacid Example 21(2S)-3-(4-{3-[(Cyclohexylmethyl)(hexyl)amino]-3-oxopropyl}phenyl)-2-ethoxypropanoicacid Example 22(2S)-3-[4-(2-{(4-Chlorobenzyl)[2-methoxybenzyl]amino}-2-oxoethoxy)phenyl]-2-ethoxypropanoicacid Example 23(2S)-3-(4-{2-[(butyl)(4-methanesulfonyloxybenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoicacid

were performed by plate chemistry.

The following compounds were prepared by one of the following methods.

Method A

Reductive Amination

1.0 ml of amine solutions was added to 0.8 ml of aldehyde solutions andthe resulting mixtures were stirred for 12 h in sealed 4 ml glass vial.

Then ca. 300 mg of borohydride resin (Aldrich 2.5 mmol/g loading) wasmanually added to the individual vials, and the mixture was stirred for8-12 h (no seal, H2-evolution; after 5 h add additional 1.0 ml of MeOH).

The mixture was filtered through a filter plate and washed once with 2.0ml of MeOH. The filtrates were collected in 24-well plates with 4 mlglass vials. Then the solvent was removed in vacuo, using the HT-4vacuum centrifuge (30° C., 5 h, vacramp).

To the residue was added polymer supported aldehyde resin (Novabiochem2.85 mmol/g loading; 80-100 mg), to remove the excess of amine and 2 mlof dry THF. The resulting mixture was stirred at rt for 6-8 h, filteredthrough a filter plate, washed once with 1.0 ml of THF and the filtratewas collected in 24-well plates with 4 ml glass vials. Then the solventwas removed in vacuo, using the HT-4 vacuum centrifuge (30° C., 5 h,vacramp).

Method B

Amide Formation {4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic acid Tothe residues were added the acid chloride solution (2.0 ml) and PS-DIEA(Argonaut 3.83 mmol/g loading; 70-80 mg) and the resulting mixture isstirred for 5-12 h.

The solutions were filtered through NH2-plates (Isolute; 500 mg) toremove any excess of acid chloride and washed with 1.0 ml THF. Thefiltrates were collected in 24-well plates with 4 ml glass vials.

If the formed amide does not contain a tertiary amino group, thesolutions are filtered through SCX-plates (Isolute; 1 g (SCX-2, PRS &SCX-3 can be used as well)) to remove the excess of secondary amine. TheSCX columns are washed with 1.0 ml of THF. The combined filtrates werecollected in 24-well plates with 4 ml glass vials.

If the formed amide does contain a tertiary amine group, polymersupported isocyanate (Novabiochem 1.5 mmol/g; ca 100 mg) was added andthe mixture was stirred for additional 6 h at RT. This is to remove anyexcess of secondary amine. Then the mixtures were filtered throughfilter plates into 247-well plates with 4 ml glass vials, followed by awash of 1.0 ml THF. The filtrates were collected in 24-well plates with4 ml glass vials. The solvent was removed in vacuum, using the HT-4vacuum centrifuge (30° C., 5 h, vacramp).

Hydrolysis

The dry residues (esters) are dissolved in 1.2 ml of THF. 400 μl of thesolution is transferred to a preweighed blue well plate. The daughterplate is analysed by LC-MS (purified by preparative HPLC if needed) andthe solvent is removed in vacuum, using the Hr-4 vacuum centrifuge (30°C., 5 h, vacramp). The dry compounds (daughter plate) are thenquantified by automatic weighing and submitted to screen.

The mother plate (containing esters dissolved in 0.8 ml THF) is treatedwith 0.8 ml 0.175M LiOH (per-vial) overnight.

If a compound contains a tertiary amine, the solution is poured onto anSCX column (Isolute; 1 g (SCX-2, PRS & SCX-3 can be used as well)) tocatch the product. The SCX columns are washed with 3×1.0 ml of THF/MeOH.Afterwards the product is eluted with 4.0 ml of MeOH, saturated withammonia.

If a compound does not contain a tertiary amine, the solvent is removedin vacuum, using the HT-4 vacuum centrifuge (30° C., 12 h, vacramp). Thedry compounds are dissolved with 11.0 ml 0.2M HCl, followed by additionof 2.0 ml of DCM. The mixtures are vigorously shaken for 30 min. Phaseseparators (6 ml, Whatman) are used to separate the DCM layer, whichcontains the product, from the water phase. The compounds are collectedin 24-well plates with 4 ml glass vials. The solvent is removed invacuum, using the HT-4 vacuum centrifuge (30° C., 5 h, vacramp).

The dry compounds are dissolved with 0.5 ml THF (or appropriate solvent)and transferred to a preweighed blue-well plate. This is repeated with0.3 ml MeOH. The solvent is afterwards removed in vacuum, using the HT-4vacuum centrifuge (30° C., 5 h, vacramp). The plate is analysed by LC-MS(purified by preparative HPLC if needed) and the dry compounds are thenquantified by automatic weighing and submitted to screen.

The following compounds were prepared by these methods:

-   (2S)-3-(4-{2-[benzyl(4-isopropylbenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic    acid-   (2S)-2-ethoxy-3-(4-{2-[(3-ethoxypropyl)(4-isopropylbenzyl)amino]-2-oxoethoxy}phenyl)propanoic    acid-   (2S)-3-(4-{2-[butyl(4-isopropylbenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic    acid-   (2S)-3-(4-{2-[(2-chlorobenzyl)(heptyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic    acid-   (2S)-2-ethoxy-3-(4-{2-[heptyl(4-isopropylbenzyl)amino]-2-oxoethoxy}phenyl)propanoic    acid-   (2S)-3-(4-{2-[[(4-cyanocyclohexyl)methyl](4-isopropylbenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic    acid-   (2S)-2-ethoxy-3-(4-{2-[(4-isopropylbenzyl)(2-methoxybenzyl)amino]-2-oxoethoxy}phenyl)propanoic    acid-   (2S)-3-(4-{2-[(2-chlorobenzyl)(4-chlorobenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic    acid-   (2S)-3-(4-{2-[(4-chlorobenzyl)(2,3-dimethoxybenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic    acid-   (2S)-3-(4-{2-[(1,3-benzodioxol-5-ylmethyl)(4-ethoxybenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic    acid-   (2S)-3-(4-{2-[(1,3-benzodioxol-5-ylmethyl)(3-bromobenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic    acid-   (2S)-3-[4-(2-{(1,3-benzodioxol-5-ylmethyl)    [3-(trifluoromethyl)benzyl]amino}-2-oxoethoxy)phenyl]-2-ethoxypropanoic    acid-   (2S)-3-(4-{2-[(3,5-dimethoxybenzyl)(4-ethoxybenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic    acid-   (2S)-3-(4-{2-[(3-chloro-4-fluorobenzyl)(4-ethoxybenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic    acid-   (2S)-2-ethoxy-3-(4-{2-[(4-ethoxybenzyl)(2-thienylmethyl)amino]-2-oxoethoxy}phenyl)propanoic    acid-   (2S)-3-(4-{2-[benzyl(isopropyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic    acid-   (2S)-3-{4-[2-(dibenzylamino)-2-oxoethoxy]phenyl}-2-ethoxypropanoic    acid-   (2S)-3-(4-{2-[bis(2-methoxyethyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic    acid-   (2S)-2-ethoxy-3-[4-(2-{heptyl[4-(trifluoromethyl)benzyl]amino}-2-oxoethoxy)phenyl]propanoic    acid-   (2S)-2-ethoxy-3-[4-(2-{heptyl[4-(trifluoromethoxy)benzyl]amino}-2-oxoethoxy)phenyl]propanoic    acid-   (2S)-2-ethoxy-3-(4-{2-[(4-ethylbenzyl)(heptyl)amino]-2-oxoethoxy}phenyl)propanoic    acid-   (2S)-3-(4-{2-[(4-tert-butylbenzyl)(heptyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic    acid-   (2S)-2-ethoxy-3-(4-{2-[heptyl(4-isobutylbenzyl)amino]-2-oxoethoxy}phenyl)propanoic    acid-   (2S)-3-(4-{2-[benzyl(heptyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic    acid-   (2S)-2-ethoxy-3-(4-{2-[(4-fluorobenzyl)(heptyl)amino]-2-oxoethoxy}phenyl)propanoic    acid-   (2S)-3-(4-{2-[(4-chlorobenzyl)(heptyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic    acid-   (2S)-3-(4-{2-[(4-bromobenzyl)(heptyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic    acid-   (2S)-3-(4-{2-[butyl(4-ethylbenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic    acid-   (2S)-3-(4-{2-[butyl(4-tert-butylbenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic    acid-   (2S)-3-(4-{2-[butyl(4-isobutylbenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic    acid-   (2S)-3-(4-{2-[benzyl(butyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic    acid-   (2S)-3-(4-{2-[butyl(4-fluorobenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic    acid-   (2S)-3-(4-{2-[(4-bromobenzyl)(butyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic    acid-   (2S)-3-(4-{2-[butyl(2,4-difluorobenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic    acid-   (2S)-3-[4-(2-{(4-chlorobenzyl)    [4-(trifluoromethoxy)benzyl]amino}-2-oxoethoxy)phenyl]-2-ethoxypropanoic    acid-   (2S)-3-(4-{2-[(4-chlorobenzyl)(4-ethylbenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic    acid-   (2S)-3-(4-{2-[(4-chlorobenzyl)(4-isobutylbenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic    acid-   (2S)-3-(4-{2-[benzyl(4-chlorobenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic    acid-   (2S)-3-(4-{2-[(4-chlorobenzyl)(4-fluorobenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic    acid-   (2S)-3-(4-{2-[(4-bromobenzyl)(4-chlorobenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic    acid-   (2S)-3-(4-{2-[(4-chlorobenzyl)(2,4-difluorobenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic    acid-   (2S)-2-ethoxy-3-[4-(2-{(4-methylbenzyl)[4-(trifluoromethyl)benzyl]amino}-2-oxoethoxy)phenyl]propanoic    acid-   (2S)-2-ethoxy-3-[4-(2-{(4-methylbenzyl)    [4-(trifluoromethoxy)benzyl]amino}-2-oxoethoxy)phenyl]propanoic acid-   (2S)-2-ethoxy-3-(4-{2-[(4-ethylbenzyl)(4-methylbenzyl)amino]-2-oxoethoxy}phenyl)propanoic    acid-   (2S)-3-(4-{2-[(4-tert-butylbenzyl)(4-methylbenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic    acid-   (2S)-2-ethoxy-3-(4-{2-[(4-isobutylbenzyl)(4-methylbenzyl)amino]-2-oxoethoxy}phenyl)propanoic    acid-   (2S)-3-(4-{2-[benzyl(4-methylbenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic    acid-   (2S)-2-ethoxy-3-(4-{2-[(4-fluorobenzyl)(4-methylbenzyl)amino]-2-oxoethoxy}phenyl)propanoic    acid-   (2S)-3-(4-{2-[(4-chlorobenzyl)(4-methylbenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic    acid-   (2S)-3-(4-{2-[(4-bromobenzyl)(4-methylbenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic    acid and-   (2S)-3-(4-{2-[(2,4-difluorobenzyl)(4-methylbenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic    acid.    Biological Activity

The compounds of the invention were tested in the assays described in WO03/051821.

Assay Procedure

Stock solutions of compounds in DMSO were diluted in appropriateconcentration ranges in master plates. From master plates, compoundswere diluted in culture media to obtain test compound solutions forfinal doses.

After adjustment of the amount of cell medium to 75 μl in each well, 50μl test compound solution was added. Transiently transfected cells wereexposed to compounds for about 24 hours before the luciferase detectionassay was performed. For luciferase assays, 100 μl of assay reagent wasadded manually to each well and plates were left for approximately 20minutes in order to allow lysis of the cells. After lysis, luciferaseactivity was measured in a 1420 Multiwell counter, Victor, from Wallach.

Reference Compounds

The TZD pioglitazone was used as reference substance for activation ofboth human and murine PPARγ. 5,8,11,14-Eicosatetrayonic acid (ETYA) wasused as reference substance for human PPARα.

Calculations and Analysis

For calculation of EC₅₀ values, a concentration-effect curve wasestablished. Values used were derived from the average of two or threeindependent measurements (after subtraction of the background averagevalue) and were expressed as the percentage of the maximal activationobtained by the reference compound. Values were plotted against thelogarithm of the test compound concentration. EC₅₀ values were estimatedby linear intercalation between the data points and calculating theconcentration required to achieve 50% of the maximal activation obtainedby the reference compound.

The compounds of formula I have an EC₅₀ of less than 0.1 μmol/l forPPARα and particular compounds have an EC₅₀ of less than 0.0 μmol/l.Additionally in particular compounds the ratio of the EC₅₀ (PPARγ): EC₅₀(PPARα) is greater than 150:1. It is believed that this ratio isimportant with respect to the pharmacological activity of the compoundsand to their therapeutic profile. Example no EC₅₀ PPARα (μM) ratio EC₅₀(PPARγ):EC₅₀ (PPARa) 12 0.003 >1000 13 0.008 >400 15 0.003 >900In addition the compounds of the present invention exhibit improved DMPK(Drug Metabolism and Pharmacokinetic) properties for example theyexhibit improved metabolic stability in-vitro. The compounds also have apromising toxicological profile.

1-18. (canceled)
 19. A compound of formula I

as well as optical isomers and racemates therof as well aspharmaceutically acceptable salts, prodrugs, solvates and crystallineforms thereof, wherein A is situated in the para position and represents

R is —OR^(a), wherein R^(a) represents hydrogen; R¹ is —OR^(e), whereinR^(e) is alkyl R² is hydrogen; R³ and R⁴ are hydrogen,; T represents O;n represents 1; R⁵ is hydrogen; R⁶ independently represent hydrogen,C₁₋₁₃alkyl, C₂₋₁₀alkenyl or C₂₋₁₀alkynyl each of which is optionallysubstituted by one or more of the following which may be the same ordifferent: C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl, aryl, heterocyclyl,heteroaryl, C₁₋₈alkoxy (optionally substituted by one or more fluoro),C₃₋₈cycloalkoxy, C₃₋₈cycloalkenyloxy, aryloxy, heterocyclyloxy,heteroaryloxy, C₃₋₈cycloalkyl C₁₋₈alkoxy, aryl C₁₋₈alkoxy, heterocyclylC₁₋₈ alkoxy or heteroaryl C₁₋₈ alkoxy, fluorine or hydroxy and whereineach of these substituents may optionally be substituted on carbon withone or more substituents which may be the same or different and selectedfrom C₁₋₈alkyl, C₃₋₈cycloalkyl (optionally substituted by C₁₋₈alkyl,C₁₋₈alkoxy (optionally substituted by one or more fluoro), halogen,hydroxy, nitro or cyano), aryl (optionally substituted by C₁₋₈alkyl,C₁₋₈alkoxy (optionally substituted by one or more fluoro), halogen,hydroxy, nitro or cyano), heterocyclyl (optionally substituted byC₁₋₆alkyl on any nitrogen), heteroaryl (optionally substituted byC₁₋₈alkyl, C₁₋₈alkoxy (optionally substituted by one or more fluoro),halogen, hydroxy, nitro or cyano), C₁₋₈alkoxy (optionally substituted byone or more fluoro), C₃₋₈cycloalkoxy, C₃₋₈ cycloalkyl C₁₋₈alkoxy,aryloxy (optionally substituted by C₁₋₈alkyl, C₁₋₈alkoxy (optionallysubstituted by one or more fluoro), halogen, hydroxy, nitro or cyano),aryl C₁₋₈alkoxy (wherein the aryl part is optionally substituted byC₁₋₈alkyl, C₁₋₈alkoxy (optionally substituted by one or more fluoro),halogen, hydroxy, nitro or cyano), halogen, amino, nitro, hydroxy,methylsulfonyl, methylsulfonyloxy, cyano or methylenedioxy, or R⁵ and R⁶independently represent C₃-C₈ cycloalkyl; C₃-C₈ cycloalkenyl; aryl;heterocyclyl; or heteroaryl; wherein each of these groups is optionallysubstituted by one or more of the following: C₁₋₈alkyl, C₁₋₈alkoxy(optionally substituted by one or more fluoro), halogen, hydroxy, nitroor cyano), aryl (optionally substituted by C₁₋₈alkyl, C₁₋₈alkoxy(optionally substituted by one or more fluoro), halogen, hydroxy, nitroor cyano; or R⁵ and R⁶ together with the nitrogen atom to which they areattached form a single or a fused heterocyclic system.
 20. A compoundaccording to claim 19; wherein, R⁶ represents; C₁₋₃alkyl, which isoptionally substituted by aryl, and wherein the aryl is optionallysubstituted on carbon with C₁₋₈alkoxy.
 21. A compound according to claim20, wherein, R⁶ represents C₁₋₁₃ alkyl, substituted by aryl, which inits turn is substituted on carbon with C₁₋₈ alkoxy.
 22. A compoundaccording to claim 19, wherein R⁵ is H.
 23. A compound according toclaim 19, wherein R⁵ is H; and R⁶ represents; C₁₋₁₃alkyl, which isoptionally substituted by aryl, and wherein the aryl is optionallysubstituted on carbon with C₁₋₈alkoxy.
 24. A compound according to claim19, wherein R⁵ is H; and R⁶ represents C₁₋₁₃ alkyl, substituted by aryl,which in its turn is substituted on carbon with C₁₋₈ alkoxy.